Implantable system enabling responsive therapy for pain

ABSTRACT

An implantable neurostimulator system for treating pain includes scheduled and responsive therapy capabilities including responsive stimulation applied to the brain and peripheral sections of the nervous system. Methods for treating chronic nociceptive, neuropathic, and psychogenic pain employ an inventive system to advantageously reduce multiple symptoms and components of pain and to address underlying causes of pain.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/374,380, which is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The invention relates to systems and methods for treating braindisorders, and more particularly to treating pain and related conditionswith automatically delivered therapies.

BACKGROUND OF THE INVENTION

Chronic pain, commonly defined as pain that lasts at least six months,is a major medical problem worldwide. Currently used treatment optionsoften fail to relieve all of a patient's symptoms and are associatedwith significant side effects. Some estimates place the burden as highas US$100 billion per year in the United States alone for the effects ofchronic pain including lost productivity and medical expenses.

Pain in general is categorized into three types. Nociceptive pain is thecentral nervous system's reaction to tissue injury. Nociceptive pain isusually time-limited and tends to decrease as the injury heals. In somecases, such as arthritis and cancer pain, it does not necessarilydecrease over time. Regardless of cause, nociceptive pain can belong-term and debilitating.

Neuropathic pain arises out of damage to the central nervous systemitself, causing signals to be erroneously interpreted as physical pain.This category of pain includes phantom limb pain in amputees and othertypes of central pain, including allodynia and hyperalgesia. Somestudies consider tinnitus, a chronic “ringing of the ears,” to be a formof neuropathic pain caused by nerve damage in the auditory system.

Some patients experience combinations of nociceptive and neuropathicpain; in many cases they are mutually reinforcing.

Psychogenic pain is either entirely psychological or without otheradequate known medical cause and is generally rare. But to the patientexperiencing psychogenic pain, it is potentially very disabling.

The therapy of first resort for nociceptive pain is typicallynonsteroidal anti-inflammatory drugs (commonly known as NSAIDs). Thiscategory of drugs includes ibuprofen (ADVIL®, MOTRIN®), naproxen(ALEVE®), and celecoxib (CELEBREX®). They work by blockingcyclooxygenase enzymes, both COX-1 and COX-2 in the case of traditionalNSAIDs (such as ibuprofen and naproxen), and primarily COX-2 in the caseof the more recent drugs (such as celecoxib). The inhibition of COX-1may lead to gastrointestinal side effects, and recently, COX-2 specificinhibitors have been linked to an increased risk of myocardialinfarction and stroke. There may also be adverse renal effects in allcases.

In more serious cases of chronic pain, opioids are frequentlyprescribed. This category of drugs includes morphine, codeine, fentanyl,and oxycodone. While treatment with opioids is frequently successful,serious side effects include sedation, respiratory depression,constipation, development of tolerance, and in many cases, addiction andabuse.

For neuropathic pain, antidepressants and anticonvulsives have beenfound to be useful. Tricyclic antidepressants such as amitriptylene,imipramine, doxepine, clomipramine and trimipramine are useful in somecases, but have significant side effects including sedation, arrhythmia,and constipation. SSRI antidepressants (fluoxetine, paroxetine, etc.)have not been found to be as effective in most cases. Anticonvulsivessuch as carbamazepine, gabapentin, and phenytoin also provide relief insome patients, but the side effects of these drugs include sedation,liver and kidney dysfunction, and aplastic anemia.

Antidepressants are also used in the treatment of neuropathic pain withsome success. As set forth above, side effects do occur.

All of the above drug therapies are useful in treating various cases ofchronic pain, but the side effect profiles and ineffectiveness for somepatients may cause drug therapy to be contraindicated in a relativelysignificant portion of the population needing relief.

Externally applied non-drug therapies such as transcutaneous electricalnerve stimulation (TENS) and acupuncture are inconvenient, as theytypically require the participation of a clinician, and may not providelong-term relief for many patients.

Implantable spinal cord and peripheral nerve stimulators arecommercially available. Some work has been done with deep brainstimulators, but such devices are generally configured to provide aconstant (or repeating intermittent) signal to a portion of the brain,which may lead to deficit in the area being stimulated or adjacentareas, and may also result in side effects. The application ofcontinuous or semi-continuous stimulation does not require aparticularly complex device, but more power is required than would benecessary in a device that stimulated only selectively. And there issome risk of habituation with chronic stimulation.

Spinal cord stimulation and to some extent TENS and implantableperipheral nerve stimulation are thought to provide relief consistentwith the “gate control” theory of pain, in which signals in large andsmall nerve fibers interact to provide pain perception. Simplified tosome extent, signals in large nerve fibers primarily representnon-painful stimuli such as touch, and tend to activate neuronsinhibiting pain. When pain is present, signals in small nerve fibersinhibit the inhibitory neurons, thereby facilitating pain perception.Spinal cord stimulation (SCS), TENS, and peripheral nerve stimulation(PNS) all tend to control the spike rate of neurons in large fibers(which are more easily activated than small fibers), thereby favoringtouch over pain. There is also differential activation of afferentnerves (ascending signals) over efferent (descending). SCS in particularis thought to act through inhibition, possibly through descendinginhibitory pathways.

Implantable drug pumps are a promising therapy for chronic pain,allowing analgesic therapeutic agents to be targeted directly on thetissue from which the pain arises. However, in many cases, implantabledrug pumps that deliver drugs outside of brain targets are ineffective.In addition to having side effects and controlled substance issues, drugpumps require maintenance and may tend to adversely affect the functionof surrounding tissue.

Studies of the brain using functional imaging techniques have identifieda number of brain regions that are involved in pain processing. Theseinclude but are not limited to the anterior cingulate cortex, prefrontalcortex, insular cortex, thalamus and portions of the somatosensorycortex, for example those corresponding to regions of pain (see, e.g.,Krause P, Forderreuther S, Straube A. TMS motor cortical brain mappingin patients with complex regional pain syndrome type I. Clin.Neurophysiol. 2006 January; 117 (1): 169-76. Epub 2005 Dec. 2; andApkarian A V, Bushnell M C, Treede R D, Zubieta J K. Human brainmechanisms of pain perception and regulation in health and disease. EurJ Pain. 2005 August; 9 (4):463-84, both incorporated by referenceherein). Accordingly, surgical and ablative techniques, performedperipherally and in the central nervous system, are gaining favor inparticularly difficult-to-control cases of chronic pain. Non-surgicalresection and ablation can be performed using radiological Gamma Knifeand linear accelerator apparatus. Great precision is required, assurgery and ablation are typically irreversible, and any deficitssustained by the patient are in many cases permanent. And even with suchgreat risks, the success of such procedures is uncertain.

Most of the approaches to treating pain set forth above have sideeffects, and even when the treatment is effective, the side effects canstill be disabling to the patient. Moreover, current treatment optionsare frequently subtherapeutic and fail to resolve the multiplecomponents of pain perception. Accordingly, there is a need for aresponsive implantable system capable of deterring, ameliorating thesymptoms of, and in some cases the underlying causes of, various chronicpain conditions.

SUMMARY OF THE INVENTION

As facilitated by the current invention, appropriate modulation of thefunction of various brain and nervous system structures can alleviatesymptoms associated with chronic pain, including nociceptive,neuropathic, and psychogenic pain. In some cases, a coordinated strategytreating multiple structures and areas may be useful to treat variouscomponents of the pain experienced by a patient.

Pain is generally regarded as having a sensory component (the localdiscomfort caused by the pain itself) and an affective component (theoverall “soreness” and discomfort associated with experiencing pain, andits motivational correlates including fear and general distress). Someresearchers also recognize a cognitive component, in which a patient'sperception of pain leads to secondary psychological effects. Knownpsychological disorders are often observed in patients with chronicpain.

In systems and methods according to the present invention, therapy forchronic pain set forth above is provided by means of a device that isable to provide responsive and programmed electrical stimulation torelevant portions of the brain and peripheral nervous system. Suchtherapy is considered effective for nociceptive, neuropathic, andpsychogenic pain, and may treat sensory, affective, and cognitivecomponents.

In an embodiment of the invention, a device is implanted in the craniumand attached to leads with electrodes at the distal end of each lead.The electrodes are placed in or adjacent to one or more structures ofinterest whether in the form of a nerve electrode, a brain depthelectrode, a plate electrode, an array of electrodes, or a brainsubdural electrode. A single electrode or multiple electrodes may beimplanted.

An embodiment of the system includes multiple devices or modules, eachoperating essentially autonomously but in a correlated fashion to treatthe various components of a patient's pain in different parts of thepatient's body or brain. In a separate embodiment, the operations of themultiple devices are coordinated by a “master device” which communicateswith, and modifies the operation of the other devices. The master devicecan be a patient controller, located external to the patient.

The system has a sensing function that responds to changes in, or adetection of, a biological marker. Such biological markers could bechanges in electrical activity, optically sensed data, changes incerebral blood flow, metabolism, and constituents, changes inconcentration of inhibitory or excitatory neurochemicals, changes inproteins or other gene products, or changes in temperature or markers ofmetabolic rate. Sensing electrodes or other sensors, including but notlimited to thermal sensors, optical sensors, and chemical detectors, areplaced over a cortical structure, within the brain, in a spinallocation, within another desired part of the patient's body or even atsome distance from an area that is to be sensed.

Responsive therapy is provided to at least one location within thecentral nervous system. Such therapy may include electrical stimulation,optical stimulation, drug delivery or changes in temperature. Inaddition, therapy delivery can be programmed by the physician or patientin response to the patient's symptoms.

It is anticipated that the part of the brain where the system sensesneural activity may be different than the location where therapy isdelivered. For example therapy may be delivered to the motor cortex orto the periventricular gray area, while the system senses in the sensoryregion of the thalamus. In this case the system is adapted to detect lowfrequency oscillatory signals in the thalamus, and to automaticallyadjust stimulation to minimize the signal representative of pain. Thedevice also includes the capability for therapy to be triggered by thepatient.

The system monitors signals representative of pain, and maintainsdiagnostics of the extent of pain over time in the patient, and theresponse of the signals representative of pain to therapy. Thediagnostics are made available to the clinician to aid in the care ofthe patient. Having a means to monitor pain without requiring thepatient to report levels of pain (which is very subjective and subjectto abuse particularly for patients on medications) is a majorimprovement in caring for these patients. In the case where the devicealso includes the capability for therapy to be triggered by the patient,the diagnostics may also keep track of the patient's requests fortherapy.

Such a system could provide benefit for those individuals with pain thatis refractory to traditional treatments and for those who experiencedrug related side effects that limit quality of life. In addition, adevice therapy as described above can be anticipated to have a morefavorable safety profile than cortical resection or cortical lesion, andwill be modifiable across individuals and over time and is reversible ifthe desired effects are not achieved. The precise portions of thepatient's brain and body over which therapy is optimally applied maydiffer from individual to individual and by the symptoms experienced.The electrodes over which therapy is applied can be adjusted accordingto the patient's short and long-term response.

An embodiment of the invention allows for the sensing and identifyingsignals representing pain in one or more of the patient's primarysomatosensory cortex (SI), secondary somatosensory cortex (SII),anterior cingulate cortex, prefrontal cortex, insular cortex, thalamus,the sensory area of the thalamus, spinal cord, and peripheral nerves.The invention further allows for treatment in one or more of thethalamus, motor cortex, brain stem, periaqueductal gray, periventriculargray, precentral gyms, cingulate, caudate, amygdala, parietal cortex,spinal cord, and peripheral nerves.

An embodiment of the device provides continuous monitoring ofelectrocorticographic signals. This capability can identify disturbancesin brain electrical activity over various portions of the brain thatcannot be adequately monitored by scalp EEG due to their distance fromthe recording electrodes and the significant filtering effect of skulland scalp. This is an especially important capability of the systembecause pain is likely to be accompanied by dynamic electrographicdisturbances. This device will also enable continuous monitoring ofother biological markers that may reveal signals of disease and diseasesymptoms. Identifying these biological markers via continued observationwith a system according to the invention will contribute to knowledgeregarding the underlying pathophysiology of these diseases and willprovide information that may open new avenues for targeted therapy.

Direct stimulation of the nervous system using a device according to theinvention provides advantages over drugs, resective and lesion-basedsurgery, and over continuous deep-brain stimulation. Targeted andselective therapy promises longer battery life. Additionally, responsivestimulation can self modulate to more adjust to the patient's changingcondition, and to deliver more optimal therapy over time. Delivery oftherapy has an effect that extends beyond the immediate duration of thetherapy. As described above, an exemplary device utilizes two leads offour electrodes each. Using either depth or subdural leads (or acombination of the two), electrodes can be applied over much of one ortwo structures of interest, and multiple modules in a system accordingto the invention can target even more structures. Within the frameworkof the implanted configuration, preferred stimulation electrodes can beconfigured over time as a patient's symptoms are observed. Stimulationmay be quite focal, using adjacent electrodes as anode and cathode, orcan be applied to relative large volumes of tissue by utilizing alleight electrodes referred to the can of the device.

Another advantage of the implantable neurostimulator system is thecapacity to apply modifiable stimulation settings. In an embodiment ofthe invention, pulse widths can be set between 40 and 1000 microseconds,pulse frequency may range between 1 and 333 Hz, and current can beadjusted between 0.5 and 12 milliamps. These settings may be set by theclinician or automatically adjusted in a responsive system. This ensuresthat patients receive effective pulse settings over changing medicalconditions while minimizing adverse effects. Non-pulsatile electricalstimulation may also be advantageously employed. It is reasonable toassume that individual patients will differ in terms of the optimalstimulus settings. Drug delivery, thermal stimulation, magneticstimulation, and optical stimulation are alternative therapy modalities.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features, and advantages of the invention willbecome apparent from the detailed description below and the accompanyingdrawings, in which:

FIG. 1 is a schematic illustration of a patient's head showing theplacement of an implantable neurostimulator according to an embodimentof the invention;

FIG. 2 is a schematic illustration of a patient's cranium showing theimplantable neurostimulator of FIG. 1 as implanted, including a leadextending to the patient's brain;

FIG. 3 is a block diagram illustrating a system context in which animplantable neurostimulator according to the invention is implanted andoperated;

FIG. 4 is a block diagram illustrating the major functional subsystemsof an implantable neurostimulator according to the invention;

FIG. 5 is a schematic representation of a human patient with multipleinterconnected implantable neurostimulator devices in an embodiment ofthe invention;

FIG. 6 is a block diagram illustrating the major functional subsystemsof a remote sensing module according to the invention;

FIG. 7 is a block diagram illustrating the major functional subsystemsof a remote therapy module according to the invention;

FIG. 8 is a block diagram illustrating the functional components of thedetection subsystem of the implantable neurostimulator shown in FIG. 4;

FIG. 9 is a block diagram illustrating the functional components of thesensing front end of the detection subsystem of FIG. 8;

FIG. 10 is a block diagram illustrating the functional components of thewaveform analyzer of the detection subsystem of FIG. 8;

FIG. 11 is a block diagram illustrating the functional arrangement ofcomponents of the waveform analysis of the detection subsystem of FIG. 8in one possible programmed embodiment of the invention;

FIG. 12 is a block diagram illustrating the functional components of thetherapy subsystem of the implantable neurostimulator shown in FIG. 4;

FIG. 13 is a block diagram illustrating the functional components of thedrug pump of the implantable neurostimulator shown in FIG. 4;

FIG. 14 is a block diagram illustrating the functional components of thecommunication subsystem shown in FIG. 4;

FIG. 15 is a flow chart setting forth an illustrative process performedby hardware and software functional components of the neurostimulator ofFIG. 4 in treating pain according to the invention;

FIG. 16 is a flow chart setting forth an illustrative process performedby hardware and software functional components of the neurostimulator ofFIG. 4, in connection with a remote sensing module according to FIG. 6and a remote therapy module according to FIG. 7 in an embodiment of theinvention;

FIG. 17 is a flow chart illustrating an illustrative signal processingflow as performed by a neurostimulator or remote sensing moduleaccording to the invention;

FIG. 18 is a flow chart illustrating a process advantageously used by asystem according to the invention to coordinate detection and actionsamong multiple neurostimulators, remote sensing modules, and remotetherapy modules according to the invention; and

FIG. 19 illustrates an exemplary set of waveforms usable forlow-frequency electrical stimulation in an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below, with reference to detailedillustrative embodiments. It will be apparent that a system according tothe invention may be embodied in a wide variety of forms. Consequently,the specific structural and functional details disclosed herein arerepresentative and do not limit the scope of the invention.

FIG. 2 depicts an intracranial implantation of an implantableneurostimulator device 110 according to the invention, which in oneembodiment is a small self-contained responsive neurostimulator. As theterm is used herein, a responsive neurostimulator is a device capable ofdetecting or predicting neurological events and conditions, such asabnormal electrical activity, and providing electrical stimulation toneural tissue in response to that activity, where the electricalstimulation is specifically intended to terminate the abnormal activity,treat a neurological event, prevent an unwanted neurological event fromoccurring, or lessen the severity or frequency of certain symptoms of aneurological disorder. Event detection can include, for example,measurement of related signatures, such as one or more pain signatures,each of which can be a component of the event that is at least partiallyrelated to a symptom of the disorder. As disclosed herein, theresponsive neurostimulator detects abnormal neurological activity in thecentral nervous system or peripheral nervous system (e.g., spine, vagusnerve, peripheral pain fibers) by systems and methods according to theinvention.

Preferably, an implantable device according to the invention is capableof detecting or predicting any kind of neurological event that has arepresentative electrographic signature, such as a pain signature. Whilethe disclosed embodiment is described primarily as responsive tosymptoms and conditions present in chronic pain, it should be recognizedthat it is also possible for a multifunction device to respond to othertypes of neurological disorders, such as epilepsy, movement disorders(e.g. the tremors characterizing Parkinson's disease), migraineheadaches, and psychiatric disorders. Preferably, neurological eventsrepresenting any or all of these afflictions can be detected when theyare actually occurring, in an onset stage, or as a predictive precursorbefore clinical symptoms begin.

In the disclosed embodiment, the neurostimulator device 110 is implantedintracranially in a patient's parietal bone 210, in a location anteriorto the lambdoid suture 212 (see FIG. 2). It should be noted, however,that the placement described and illustrated herein is merely exemplary,and other locations and configurations are also possible, in the craniumor elsewhere, depending on the size and shape of the device andindividual patient needs, among other factors. The device 110 ispreferably configured to fit the contours of the patient's cranium 214.In an alternative embodiment, the device 110 is implanted under thepatient's scalp 112 (FIG. 1) but partially or fully external to thecranium; it is expected, however, that this configuration wouldgenerally cause an undesirable protrusion in the patient's scalp wherethe device is located. In yet another alternative embodiment, when it isnot possible to implant the device intracranially, it may be implantedpectorally (not shown), with leads extending through the patient's neckand between the patient's cranium and scalp, as necessary.

It should be recognized that the embodiment of the device 110 describedand illustrated herein is preferably a responsive neurostimulator fordetecting and treating pain, chronic pain and related symptoms,including psychological, emotional, sensory, and cognitive effects, bydetecting neurophysiological signatures of related conditions, symptoms,or their onsets or precursors, and preventing and/or relieving suchconditions and symptoms.

In an alternative embodiment of the invention, the device 110 is not aresponsive neurostimulator, but is an apparatus capable of detectingsignatures of neurological conditions and events and performing actions(other than electrical stimulation) in response thereto. For example,the actions performed by such an embodiment of the device 110 need notbe therapeutic, but may only involve data recording or transmission,providing warnings to the patient, providing a patient with messages(e.g., “take medication” or “your depression score is increasing”),alerting a physician, or any of a number of known alternative actions.Additionally, using an external patient programmer, the patient caninduce data collection when subjective experiences occur and can enterevent tags (e.g., “pain has decreased” or “feel depressed”). Such adevice will typically act as a diagnostic device when interfaced withexternal equipment. A device according to the invention, whether itdelivers therapy or acts solely as a diagnostic device, isadvantageously capable of storing diagnostic information for laterretrieval by a programmer.

The device 110, as implanted intracranially, is illustrated in greaterdetail in FIG. 2. The device 110 is affixed in the patient's cranium 214by way of a ferrule 216. The ferrule 216 is a structural member adaptedto fit into a cranial opening, attach to the cranium 214, and retain thedevice 110.

To implant the device 110, a craniotomy is performed in the parietalbone 310 anterior to the lambdoid suture 212 to define an opening 218slightly larger than the device 110. The ferrule 216 is inserted intothe opening 218 and affixed to the cranium 214, ensuring a tight andsecure fit. The device 110 is then inserted into and affixed to theferrule 216.

As shown in FIG. 2, the device 110 includes a lead connector 220 adaptedto receive one or more electrical leads, such as a first lead 222. Thelead connector 220 acts to physically secure the lead 222 to the device110, and facilitates electrical connection between a conductor in thelead 222 coupling an electrode to circuitry within the device 110. Thelead connector 220 accomplishes this in a substantially fluid-tightenvironment with biocompatible materials.

The lead 222, as illustrated, and other leads for use in a system ormethod according to the invention, is a flexible elongated member havingone or more conductors. As shown, the lead 222 is coupled to the device110 via the lead connector 220, and is generally situated on the outersurface of the cranium 214 (and under the patient's scalp 112),extending between the device 110 and a burr hole 224 or other cranialopening, where the lead 222 enters the cranium 214 and is coupled to adepth electrode or other sensor (e.g., one of the sensors 412-418 ofFIG. 4) implanted in a desired location in the patient's brain. If thelength of the lead 222 is substantially greater than the distancebetween the device 110 and the burr hole 224, any excess may be urgedinto a coil configuration under the scalp 112. As described in U.S. Pat.No. 6,006,124 to Fischell, et al. for “Means and Methods for thePlacement of Brain Electrodes” issued Dec. 21, 1999, which is herebyincorporated by reference as though set forth in full herein, the burrhole 224 is sealed after implantation to prevent further movement of thelead 222; in an embodiment of the invention, a burr hole cover apparatusis affixed to the cranium 214 at least partially within the burr hole224 to provide this functionality.

The device 110 includes a durable outer housing 226 fabricated from abiocompatible material. Titanium, which is light, extremely strong, andbiocompatible, is used in analogous devices, such as cardiac pacemakers,and would serve advantageously in this context. As the device 110 isself-contained, the housing 226 encloses a battery and any electroniccircuitry necessary or desirable to provide the functionality describedherein, as well as any other features. As will be described in furtherdetail below, a telemetry coil may be in the interior of the device 110or provided outside of the housing 226 (and potentially integrated withthe lead connector 220) to facilitate communication between the device110 and external devices.

The neurostimulator configuration described herein and illustrated inFIG. 2 provides several advantages over alternative designs. First, theself-contained nature of the neurostimulator substantially decreases theneed for access to the device 110, allowing the patient to participatein normal life activities. Its small size and intracranial placementcauses a minimum of cosmetic disfigurement. The device 110 will fit inan opening in the patient's cranium, under the patient's scalp, withlittle noticeable protrusion or bulge. The ferrule 216 used forimplantation allows the craniotomy to be performed and fit verifiedwithout the possibility of breaking the device 110, and also providesprotection against the device 110 being pushed into the brain underexternal pressure or impact. A further advantage is that the ferrule 216receives any cranial bone growth, so at explant, the device 110 can bereplaced without removing any bone screws—only the fasteners retainingthe device 110 in the ferrule 216 need be manipulated.

As will be discussed in further detail below, the leads attached to thedevice 110 are implanted in one or more structures of interest, in thebrain (including cortical structures and deep brain structures), otherportions of the central nervous system, and the peripheral nervoussystem. It will be noted that lead placement is patient specific;different symptoms and conditions call for different structures to betargeted—for example, patients with central pain may benefit primarilyfrom central stimulation, and patients with peripheral pain (i.e.,nociceptive pain arising from peripheral locations) may benefit fromperipheral nerve stimulation. Patients with idiopathic pain (i.e., painwith no known cause) may benefit from some combination of central andperipheral stimulation depending on the patient's individual clinicalcircumstances. This will be discussed in further detail below.

As stated above, and as illustrated in FIG. 3, a neurostimulatoraccording to the invention operates in conjunction with externalequipment. The implantable neurostimulator device 110 is mostlyautonomous (particularly when performing its usual sensing, detection,and stimulation capabilities), but preferably includes a selectablepart-time wireless link 310 to external equipment such as a programmer312. In the disclosed embodiment of the invention, the wireless link 310is established by moving a wand (or other apparatus) havingcommunication capabilities and coupled to the programmer 312 intocommunication range of the implantable neurostimulator device 110. Theprogrammer 312 can then be used to manually control the operation of thedevice, as well as to transmit information to or receive informationfrom the implantable neurostimulator 110. Several specific capabilitiesand operations performed by the programmer 312 in conjunction with thedevice will be described in further detail below.

The programmer 312 is capable of performing a number of advantageousoperations in connection with the invention. In particular, theprogrammer 312 is able to specify and set variable parameters in theimplantable neurostimulator device 110 to adapt the function of thedevice to meet the patient's needs, upload or receive data sent from theimplantable neurostimulator 110 to the programmer 312 including, but notlimited to, stored sensed data such as raw signal waveforms (e.g.,collected before and after stimulation, continuously, or periodically),summaries of the sensed information (e.g., statistical summaries such asmean and standard deviation of the count, kind, size, or other aspect ofdetected events; a count of detected events) parameters, storeddiagnostic information relating to observed activity, or logs of actionstaken. The programmer 312 can also download or transmit program code andother information to the implantable neurostimulator 110, or command theimplantable neurostimulator 110 to perform specific actions or changestimulation, treatment, or recording modes as desired by a physicianoperating the programmer 312. To facilitate these functions, theprogrammer 312 is adapted to receive clinician input 314 and provideclinician output 316; data is transmitted between the programmer 312 andthe implantable neurostimulator 110 over the wireless link 310.

The programmer 312 may be used at a location remote from the implantableneurostimulator 110 if the wireless link 310 is enabled to transmit dataover long distances. For example, the wireless link 310 may beestablished by a short-distance first link between the implantableneurostimulator 110 and a transceiver, with the transceiver enabled torelay communications over long distances to a remote programmer 312,either wirelessly (for example, over a wireless computer network) or viaa wired communications link (such as a telephonic circuit or a computernetwork).

The programmer 312 may also be coupled via a communication link 318 to anetwork 320 such as the Internet. This allows any information uploadedfrom the implantable neurostimulator 110, as well as any program code orother information to be downloaded to the implantable neurostimulator110, to be stored in a database 322 at one or more data repositorylocations (which may include various servers and network-connectedprogrammers like the programmer 312). This would allow a patient (andthe patient's physician) to have access to important data, includingpast treatment information and software updates, essentially anywhere inthe world where there is a programmer (like the programmer 312) and anetwork connection. Alternatively, the programmer 312 may be connectedto the database 322 over a trans-telephonic link such as modemconnection.

In yet another alternative embodiment of the invention, the wirelesslink 310 from the implantable neurostimulator 110 may enable a transferof data from the neurostimulator 110 to the database 322 without anyinvolvement by the programmer 312. In this embodiment, as with others,the wireless link 310 may be established by a short-distance first linkbetween the implantable neurostimulator 110 and a transceiver (such as aBluetooth® enabled modem with a wireless port for accepting data or adevice operating in the MICS band), with the transceiver enabled torelay communications over long distances to the database 322, eitherwirelessly (for example, over a wireless computer network) or via awired communications link (such as trans-telephonically over atelephonic circuit, or over a computer network).

In the disclosed embodiment, the implantable neurostimulator 110 is alsoadapted to receive communications from an initiating device 324,typically controlled by the patient or a caregiver. Accordingly, patientinput 326 from the initiating device 324 is transmitted over a wirelesslink to the implantable neurostimulator 110; such patient input 326 maybe used to cause the implantable neurostimulator 110 to switch modes (onto off and vice versa, for example) or perform an action (e.g., store arecord of signal waveform data along with a timestamp and comment fromthe user). Preferably, the initiating device 324 is able to communicatewith the implantable neurostimulator 110 through a communicationsubsystem 430 (FIG. 4), and possibly via the same kind of link as theprogrammer 312. The link may be unidirectional (as with the magnet andGMR sensor described below), allowing commands to be passed in a singledirection from the initiating device 324 to the implantableneurostimulator 110, but in an alternative embodiment of the inventionis bi-directional, allowing status and data to be passed back to theinitiating device 324. Accordingly, the initiating device 324 may be aprogrammable PDA or other hand-held computing device, such as a Palm®device or PocketPC®. Additionally, the initiating device may becompatible with Flash or USB ports and can include wirelesscommunication capabilities so that any computer, PDA, or similarapparatus can be used by the patient to communicate with theneurostimulator device 110. However, a simple form of initiating device324 may take the form of a permanent magnet, if the communicationsubsystem 430 (FIG. 4) is adapted to identify magnetic fields andinterruptions therein as communication signals.

The implantable neurostimulator 110 (FIG. 1) generally interacts withthe programmer 312 (FIG. 3) as described below. Data stored in a memorysubsystem 426 (FIG. 4) of the device 110 can be retrieved by thepatient's physician through the wireless communication link 310, whichoperates through the communication subsystem 430 of the implantableneurostimulator 110. In connection with the invention, a softwareoperating program run by the programmer 312 allows the physician to readout a history of neurological events detected including signalinformation before, during, and after each neurological event, as wellas specific information relating to the detection of each neurologicalevent (such as, in one embodiment, the time-evolving energy spectrum ofthe patient's observed signal across at least a portion of a“spectrogram”). The programmer 312 also allows the physician to specifyor alter any programmable parameters of the implantable neurostimulator110. The software operating program also includes tools for the analysisand processing of recorded signals to assist the physician in developingoptimized detection parameters for detecting pain, depression or seizuresignatures in each specific patient.

In an embodiment of the invention, the programmer 312 is primarily acommercially available PC, laptop computer, or workstation having a CPU,memory, keyboard, mouse and display, and running a standard operatingsystem such as Microsoft Windows®, Linux®, Unix®, or Apple Mac OS®. Itis also envisioned that a dedicated programmer apparatus with a customsoftware package (which may not use a standard operating system) couldbe developed. Alternatively, in an alternative embodiment the programmer312 is a computer or PDA capable of communicating with a programresiding on a remote server that sends and receives data from theprogrammer 312. In this instance the programmer 312 is realizedpartially as a web-based virtual instrument using a local computer forinteracting with the physician/patient and the implanted neurostimulator110.

When running the computer workstation software operating program, theprogrammer 312 can process, score, measure, classify, detect eventswithin, and states based upon, sensed signals, and can store, play backand display the patient's electrographic or other sensor signals, aspreviously stored by the implantable neurostimulator 110 of theimplantable neurostimulator device.

The computer workstation software program also has the capability tosimulate the detection and prediction of abnormal electrical activityand other symptoms and results of chronic pain. Furthermore, thesoftware program of the present invention has the capability to allow aclinician to create or modify a patient-specific collection ofinformation comprising, in one embodiment, algorithms and algorithmparameters for detection of specific types of activity. The results oftailoring patient-specific detection algorithms and parameters used forneurological activity detection according to the invention will bereferred to herein as a detection template or patient-specific template.The patient-specific template, in conjunction with other information andparameters generally transferred from the programmer to the implanteddevice (such as stimulation parameters, treatment schedules, and otherpatient-specific information), make up a set of operational parametersfor the neurostimulator.

Following the development of a patient-specific template on theprogrammer 312, the patient-specific template would be downloadedthrough the communications link 310 from the programmer 312 to theimplantable neurostimulator 110.

The patient-specific template is used by a detection subsystem 422 andCPU 428 (FIG. 4) of the implantable neurostimulator 110 to detectconditions indicating treatment should be administered, and can beprogrammed by a clinician to result in responsive stimulation of thepatient's brain, as well as the storage of sensed signals before andafter the detection, facilitating later clinician review.

Preferably, the database 322 is adapted to communicate over the network320 with multiple programmers, including the programmer 312 andadditional programmers 328, 330, and 332. It is contemplated thatprogrammers will be located at various medical facilities andphysicians' offices at widely distributed locations. Accordingly, ifmore than one programmer has been used to upload stored signals from apatient's implantable neurostimulator 110, the stored signals will beaggregated via the database 322 and available thereafter to any of theprogrammers connected to the network 320, including the programmer 312.

FIG. 4 is an overall block diagram of the implantable neurostimulatordevice 110 used for measurement, detection, and treatment according tothe invention. Inside the housing of the neurostimulator device 110 areseveral subsystems making up the device. The implantable neurostimulatordevice 110 is capable of being coupled to a plurality of sensors 412,414, 416, and 418 (each of which may be individually or togetherconnected to the implantable neurostimulator device 110 via one or moreleads or which may communicate with the device via telemetry), which inan embodiment of the invention are electrodes used for both sensing andstimulation, or may include transducers and outputs for the delivery ofother treatment modalities. In the illustrated embodiment, the couplingis accomplished through a lead connector.

Although four sensors are shown in FIG. 4, it should be recognized thatany number is possible, and in an embodiment described in detail herein,eight electrodes are used as sensors. In fact, it is possible to employan embodiment of the invention that uses a single lead with at least twoelectrodes, or two leads each with a single electrode (or with a secondelectrode provided by a conductive exterior portion of the housing inone embodiment), although bipolar sensing between two closely spacedelectrodes on a lead is preferred to minimize common mode signalsincluding noise. In an alternate embodiment of the invention, sensingand/or stimulation electrodes are used in combination with sensors, suchas temperature and blood flow sensors, as will be described below.

The sensors 412, 414, 416 and 418 are in contact with the patient'sbrain or are otherwise advantageously located to receive signals (e.g.,EEG) or provide electrical stimulation or another therapeutic modality(e.g., optical). In an embodiment of the invention, one or more of thesensors 412, 414, 416 and 418 can be a biosensor, an optical sensor, anelectrochemical sensor, a temperature sensor, or any of a number ofsensor types capable of measuring cerebral blood flow, oxygenation,oxygen utilization, or any other local physiological condition ofinterest. See U.S. Pat. No. 7,341,562 to Pless et al. for “Modulationand Analysis of Cerebral Perfusion in Epilepsy and Other NeurologicalDisorders,” which is hereby incorporated by reference as though setforth in full herein.

Each of the sensors 412, 414, 416 and 418 is coupled to a sensorinterface 420, either electrically or via telemetry. Preferably, thesensor interface is capable of selecting electrodes as required forsensing and stimulation; accordingly the sensor interface is coupled toa detection subsystem 422 and a therapy subsystem 424 (which, in variousembodiments of the invention, may provide electrical stimulation andother therapies). The sensor interface 420 may also provide any otherfeatures, capabilities, or aspects, including but not limited toamplification, isolation, impedance measurement, and charge-balancingfunctions, that are required for a proper interface with neurologicaltissue and not provided by any other subsystem of the device 110.

In an embodiment of the invention in which electrical signals arereceived by electrodes and analyzed, the detection subsystem 422includes and serves primarily as a waveform analyzer. It will berecognized that similar principles apply to the analysis of other typesof waveforms received from other types of sensors. Detection isgenerally accomplished in conjunction with a central processing unit(CPU) 428. The waveform analyzer function of the detection subsystem 422is adapted to receive signals from the sensors 412, 414, 416 and 418,through the sensor interface 420, and to process those signals toidentify abnormal neurological activity characteristic or “signature” ofa disease or symptom thereof. One way to implement such waveformanalysis functionality is disclosed in detail in U.S. Pat. No. 6,016,449to Fischell et al. for “System for Treatment of Neurological Disorders”issued Jan. 18, 2000, incorporated by reference above. Additionalinventive methods are described in U.S. Pat. No. 6,810,285 to Pless etal. for “Seizure Sensing and Detection Using an Implantable Device”issued Oct. 26, 2004, of which relevant details will be set forth below(and which is also hereby incorporated by reference as though set forthin full). The detection subsystem may optionally also contain furthersensing and detection capabilities, including but not limited toparameters derived from other physiological conditions (such aselectrophysiological parameters, temperature, blood pressure,neurochemical concentration, etc.). In general, prior to analysis, thedetection subsystem performs amplification, analog to digitalconversion, and multiplexing functions on the signals in the sensingchannels received from the sensors 412, 414, 416 and 418.

The therapy subsystem 424 is capable of applying electrical stimulationor other therapies to neurological tissue. This can be accomplished inany of a number of different manners. For example, it may beadvantageous in some circumstances to provide stimulation in the form ofa substantially continuous stream of pulses, or on a scheduled basis. Inan embodiment of the invention, scheduled therapy (such as stimulationvia biphasic pulses or other waveforms, such as low-frequency sinewaves) can be performed by the device 110 in addition to and independentof responsive therapy. Preferably, therapeutic stimulation is providedin response to abnormal neurological events or conditions detected bythe waveform analyzer function of the detection subsystem 422. Asillustrated in FIG. 4, the therapy subsystem 424 and the signal analyzerfunction of the detection subsystem 422 are in communication; thisfacilitates the ability of therapy subsystem 424 to provide responsiveelectrical stimulation and other therapies, as well as an ability of thedetection subsystem 422 to blank the amplifiers while electricalstimulation is being performed to minimize stimulation artifacts. It iscontemplated that the parameters of a stimulation signal (e.g.,frequency, duration, waveform) provided by the therapy subsystem 424would be specified by other subsystems in the implantable device 110, aswill be described in further detail below.

In accordance with the invention, the therapy subsystem 424 may alsoprovide for other types of stimulation, besides electrical stimulationdescribed above. In particular, in certain circumstances, it may beadvantageous to provide audio, visual, or tactile signals to thepatient, to provide somatosensory electrical stimulation to locationsother than areas of the brain (e.g. sensory cortices), or to deliver adrug or other therapeutic agent (either alone or in conjunction withelectrical stimulation). Any of these therapies can be provided in anon-responsive therapy modality, such as scheduled therapy, either aloneor in combination with a responsive therapy regimen.

Also the implantable neurostimulator device 110 contains a memorysubsystem 426 and the CPU 428, which can take the form of amicrocontroller. The memory subsystem is coupled to the detectionsubsystem 422 (e.g., for receiving and storing data representative ofsensed electrographic or other signals and evoked responses), thetherapy subsystem 424 (e.g., for providing stimulation waveformparameters to the therapy subsystem for electrical stimulation), and theCPU 428, which can control the operation of (and store and retrieve datafrom) the memory subsystem 426. In addition to the memory subsystem 426,the CPU 428 is also connected to the detection subsystem 422 and thetherapy subsystem 424 for direct control of those subsystems.

Also provided in the implantable neurostimulator device 110, and coupledto the memory subsystem 426 and the CPU 428, is a communicationsubsystem 430. The communication subsystem 430 enables communicationbetween the device 110 and the outside world, particularly an externalprogrammer 312 and a patient initiating device 324, both of which aredescribed above with reference to FIG. 3. In an embodiment of theinvention, described below, the communication subsystem 430 alsofacilitates communication with other implanted devices.

Several support components are present in the implantableneurostimulator device 10, including a power supply 432 and a clocksupply 434. The power supply 432 supplies the voltages and currentsnecessary for each of the other subsystems. The clock supply 434supplies substantially all of the other subsystems with any clock andtiming signals necessary for their operation, including a real-timeclock signal to coordinate programmed and scheduled actions and thetimer functionality used by the detection subsystem 422 that isdescribed in detail below.

In an embodiment of the invention, the therapy subsystem 424 is coupledto a thermal stimulator 436 and a drug dispenser 438, thereby enablingtherapy modalities other than electrical stimulation. These additionaltreatment modalities will be discussed further below. The thermalstimulator 436 and the drug dispenser 438 are coupled to respectiveoutputs, such as a thermal conductor/generator 440 and a catheter 442,positioned at a desired location. Any of the therapies delivered by thetherapy subsystem 424 is delivered to a therapy output at a specificsite; it will be recognized that the therapy output may be a stimulationelectrode, a drug dispenser outlet, a magnetic stimulator, atranscranial magnetic stimulator, an optical stimulator, or a thermalstimulator (e.g., Peltier junction or thermocouple) as appropriate forthe selected modality.

The therapy subsystem 424 is further coupled to an optical stimulator444 and a fiber optic lead 446, enabling optical stimulation of neuralstructures in the brain, spinal cord, and nerves. Generally, the opticalstimulator 444 includes a controllable light emitter (such as at leastone LED or laser diode) that is situated onboard or in close proximityto the device 110, and the light is transmitted to the stimulation sitevia the fiber optic lead 446. Alternatively, the optical generator canbe located at least partially external to the patient, with the fiberoptic lead used to bring the light to the target region. One or morelenses may be used at the proximal or distal ends of the fiber opticlead 446, for example, to increase light collection from the emitter (atthe proximal end) and to focus the optical stimulation (at the distalend). It is understood that optical stimulation intensity is a functionof both wavelength and intensity; different patients and differenttargets will react differently to different light colors, intensities,stimulation pulse widths, and stimulation burst durations (where pulsetrains are delivered).

It should be observed that while the memory subsystem 426 is illustratedin FIG. 4 as a separate functional subsystem, the other subsystems mayalso require various amounts of memory to perform the functionsdescribed above and others. Furthermore, while the implantableneurostimulator device 110 is preferably a single physical unit (i.e., acontrol module) contained within a single implantable physicalenclosure, namely the housing described above, other embodiments of theinvention might be configured differently. The neurostimulator 110 maybe provided as an external unit not adapted for implantation, or it maycomprise a plurality of spatially separate units each performing asubset of the capabilities described above, some or all of which mightbe external devices not suitable for implantation. A transcranialmagnetic stimulator may be used and may provide responsive therapy byworking in conjunction with implanted sensors. Also, it should be notedthat the various functions and capabilities of the subsystems describedabove may be performed by electronic hardware, computer software (orfirmware), or a combination thereof. The division of work between theCPU 428 and the other functional subsystems may also vary—the functionaldistinctions illustrated in FIG. 4 may not reflect the partitioning andintegration of functions in a real-world system or method according tothe invention.

In an embodiment of the invention, multiple implanted and coordinatedmodules are employed to treat pain at multiple sites. This embodiment isillustrated in FIG. 5. In the illustration, a first implanted module 510is located in the patient's cranium (as shown in FIGS. 1-2) and isconfigured to provide deep brain and/or cortical, and continuous and/orresponsive, stimulation according to the invention. Additional modulesmay be used to augment therapeutic benefit of stimulation. For example,in one embodiment a second implanted module 512 is implanted in tissuenear the patient's spinal column, a third implanted module 514 isimplanted in tissue near a proximal end of a peripheral nerve, and afourth implanted module 516 is implanted in tissue near a distal end ofa peripheral nerve. In practice, two or more implanted modules can becoordinated according to the invention. Such coordinated therapy canentail stimulating jointly to decrease unwanted symptoms, or stimulatingat different locations to treat different symptoms, and/or stimulatingat different locations based upon the signatures detected by evaluationof sensed signals.

In the disclosed embodiment, the first implanted module 510 is a masterdevice, coordinating the actions of the remaining modules. Each of thesecond, third, and fourth modules 512, 514 and 516 in an embodiment ofthe invention may comprise a duplicate of the master device butconfigured to receive coordination commands from the master device 510,or may comprise a remote sensor module (as illustrated in FIG. 6) or aremote therapy module (as illustrated in FIG. 7). The second implantedmodule 512 may be configured primarily as a sensor to receive signalsfrom one or more locations of the spinal column, provide coordinatedspinal cord stimulation (SCS), or both. The third implanted module 514may be configured to receive signals from the peripheral nerve, providecoordinate peripheral nerve stimulation (PNS), or both. The fourthimplanted module 516 may be configured to receive signals from a moredistal section of the peripheral nerve or other nearby physiologicalindicators, provide PNS, or both. Consequently then, with multipleimplanted modules according to the invention, brain stimulation, spinalcord stimulation, and peripheral nerve stimulation can be delivered andemployed in a coordinated treatment regimen to provide the best possiblepain relief to the patient, relieving sensory, affective, and cognitivecomponents of the pain. The multiple implanted modulates can eachprovide sensing and stimulation for single or multiple modalities.

As set forth above, sensing of signals according to the invention may beperformed in one or more bilateral or unilateral locations of thepatient's primary somatosensory cortex (SI), secondary somatosensorycortex (SII), anterior cingulate cortex, prefrontal cortex, anteriorinsular cortex, thalamus, sensory thalamus, spinal cord, and peripheralnerves. Certain types of endogenous activity signatures from the SI areaare believed correlated primarily with the sensory component of pain,facilitating localization of pain. The SII area, cingulate cortex,prefrontal cortex, and insular cortex are primarily associated with theaffective component, with the cingulate cortex also particularlyinvolved in the cognitive and psychological aspects of pain processing.The thalamus is involved in both sensory and affective components, as itserves as a central mediating structure for pain perception (e.g.sensory gating). The spinal cord and peripheral nerves are involved inthe transmission of pain signals from the peripheral nervous system tothe brain, and hence are implicated in nearly all nociceptive andneuropathic pain processing. In some cases, abnormal activity may alsobe observed in the striatum, cerebellum, and supplementary motor area.In general, it is not known whether activity in these areas reflects thenervous system receiving and processing pain or an attempt to modulatethe pain through descending inhibitory mechanisms. It should be notedthat other structures not listed may also play a role in both normal andpathological pain processing and perception.

Treatment may be performed to modulate one or more of the thalamus,motor cortex, brain stem, periaqueductal gray (PAG), periventriculargray (PVG), precentral gyms, parietal cortex, spinal cord, andperipheral nerves. The PAG area, in particular, is part of the midbrainand is postulated to be a central point of control for the affectivecomponent of pain in the cortex. Localized stimulation in the motorcortex tends to regulate the sensory component. Other structures,including some not specifically listed, may modulate sensory and/oraffective components in various proportions. These structures may beidentified by clinical observations, noting response to different druginterventions, patient histories, and by various neuroimaging methodswhich can be performed in conjunction with sensory stimulation, tasks,and interventions. The structures can also be identified during theimplantation procedure based upon electrophysiological or neurochemicalsignatures which reflect abnormal levels or patterns of basal or evokedactivity. The mechanism of action is believed to be consistent with the“gate control” theory of pain as described above.

In an embodiment of the invention, as illustrated in FIG. 5, a device ispositioned relatively near each anatomic structure sought to be a sourceof information or a target of treatment. Positioning devices nearstructures of interest allows shorter leads to be used between devicesand their sensors, thereby reducing the risk of mechanical failure andalso reducing surgery complexity and scope.

Several exemplary clinical scenarios are set forth below.

For central pain, it has been found that regular oscillatory signalsobservable in the sensory thalamus may correlate with pain treatable bystimulation in the periventricular gray (PVG). See, e.g., D. Nandi etal., “Thalamic field potentials in chronic central pain treated byperiventricular gray stimulation—a series of eight cases,” Pain 101(2003) 97-107. Accordingly, then, in an embodiment of the invention, acranially implanted device is tuned to identify ECoG activity primarilyin the range of 0.1 to 1.0 Hz (most such observed activity falls in therange of 0.2-0.4 Hz). In particular, a device 110 may use an analog ordigital band-pass filter and integrator, or a half wave detection tool(with a relatively high hysteresis value as described below) tospecifically identify/measure high-amplitude activity in the frequencyrange of interest and ignore normal higher frequency activity; theoscillation frequency is generally a patient-specific determination.Alternatively, an area-based detection tool (also described below) mayalso be used.

When spectral analyses are applied to sensed signals, the duration ofwindowed data becomes an issue in connection with frequency resolution.By way of example, in order to obtain estimates of spectral energyspanning 0.2 Hz, the data must be collected in at least 5 second samplewindows. While signal processing methods such as zero-tapering, waveletdecomposition, and moving averages may be used to shorten this effectivesampling window, these may be prone to spectral leakage, in that energyat nearby frequencies may leak into the band which is being measured.Accordingly, in one embodiment, assessment of stimulation will requireevaluation of signals as these are assessed in approximately 4 to 10second samples. A mean and standard deviation can be calculated upon aspecified number of samples prior to stimulation, and stimulation can beguided in order to produce a statistically significant reduction inspectral power within a specified 0.2 Hz band. The band may be chosen bycomparing an individual's demographic data to that of an age and sexmatched normative data set collected either during pain or in theabsence of pain. The spectral band can also be chosen based upon aself-norm where activity is measured during pain and in the absence ofpain, or by comparing activity within region or spectral band toactivity in a different region of a patient, or in a different band ofspectral power. In other words, the spectral estimate can be an absoluteor relative measure such as Delta 1 power, relative Delta 1 power (i.e.divided by total power) or Delta1/Delta2 ratio. The center frequency ofthe measured band as well as its width can be determined in a number ofmanners such as looking at the shape, variance, and covariance ofspectral energy within the computed EEG spectra.

Another alternative is to use one or more analog or digital band-passfilters which are tuned to at least one frequency range of interest inorder to capture the neurophysiological signature of the pain symptom.For instance, a bandpass filter can be used which passes spectral energybetween 0.2 Hz and 0.4 Hz. This would be appropriate when the peak ofspectral energy related to the pain signal occurred at about 0.3 Hz, andwas narrow band. However, physiological signals often deviate in theircenter frequency over time, and therefore while often having a centerfrequency of 0.3 Hz, the peak energy could occur at 0.4 or 0.45 Hz whichwould be outside of the range of the filter. Accordingly, using a smallbank of band-pass filters permits the measurement of power even when thepeak frequency fluctuates somewhat over time.

One method for responsively treating pain with an implantable deviceincludes sensing a signal from an implanted sensor (for example, asensor in the thalamus), analyzing the signal to detect a pain signaturein the signal, and providing stimulation when this is detected. In oneembodiment, one or more bands of narrow band power within a specifiedrange are measured and a pain signature is detected when selectedspectral energy meets a specified criterion. For example, 10 narrowband-pass filters, each having center frequencies separated by 0.2 Hz,and ranging from 0.5 and 2.5 Hz, can be implemented to providecontinuous estimates of narrow band spectral power over that frequencyrange. In order to track the pain signal, the filter having the maximumspectral power can be selected and, if the power is above a specifiedlevel, then a pain signature is detected. Alternatively, spectral powermay always be measured in the same narrow band-frequency. The power maybe compared to a specified threshold, a self-norm, spectral power atother frequencies, or spectral power at other sensors. For example, whensensors are located to sense from regions of the somatosensory cortex,the EEG for an electrode located more proximal to a region experiencingpain (EEGp) can be compared to the EEG of neighboring electrodes (EEGn)in order to detect a relevant pain signature (e.g., spectral power ofselected bands of EEGp/EEGn, or coherence computed between EEGp and EEGnwhich may be compared to coherence computed between one or more spectralbands of two or more EEGn's).

It would be particularly advantageous to implant a lead with electrodesin the thalamus (specifically the ventroposterolateral thalamic nucleus,or VPL) and observe the particular spectral changes which occur as thepatient experiences pain and pain relief, such as an increase ordecrease of power within at least one frequency band. Alternatively, oradditionally, methods of pattern or waveform recognition may be used todetect and measure physiological signatures associated with symptoms ofthe pain disorder. Further, both increases and decreases in power,across different bands, may be representative of a pain signature(Sarnthein J, Stern J, Aufenberg C, Rousson V, Jeanmonod D. IncreasedEEG power and slowed dominant frequency in patients with neurogenicpain. Brain. 2006 January; 129 (Pt 1):55-64, incorporated by referenceherein), as can increases in coherence (Drewes A M, Sami S A, DimcevskiG, Nielsen K D, Funch-Jensen P, Valeriani M, Arendt-Nielsen L. Cerebralprocessing of painful oesophageal stimulation. A study based onindependent component analysis of the EEG. Gut. 2005), and changes inmeasures of complexity/chaos. These deviations from the values thatoccur in normative data can be evaluated by multivariate equations toproduce scores reflective of the pain. Such a measure could be theMahalanobis Distance of selected spectral regions compared to a self orpopulation norm. Generally, concurrently and in a single surgerysession, a therapy lead would be implanted in the PVG, at least oneimplantable module would be implanted and connected to the leads, andsubsequently the patient's wounds would be closed. Following surgery,all further programming and tuning of the device can be accomplished viadata telemetry.

Stimulation, generally occurring as charge-balanced biphasic waveforms(pulsatile or non-pulsatile waveforms, as described below), is thenapplied to the PVG in response to observed thalamic oscillations. Inaddition to suppressing the patient's symptoms, this also results in thesuppression of the thalamic oscillations. Effective stimulationfrequencies have been found to range from 5 to 35 Hz; for purposes ofthis disclosure, it is believed that stimulation (e.g., using pulsatileor non-pulsatile modulations, repetitions, rates or frequencies) from0.2 to 200 Hz may be effective in various patients. Differentstimulation frequencies may be selected according to the invention andapplied while activity in the thalamus continues to be observed;stimulation frequencies that best suppress the thalamic oscillationsdetermined to be signatures of (i.e., correlated with) the pain symptomsare considered to be the most effective stimulation frequencies for painrelief as well.

The duration of pain relief and of the suppression of low-frequencythalamic activity has been found to extend 5-15 minutes, and potentiallylonger, past the application of therapeutic stimulation. Accordingly,then, a system according to the invention is programmed to apply aninterval of stimulation upon the observation of a pain signature such asa low frequency thalamic oscillation exceeding a programmed amplitudethreshold. The duration of the therapy interval may depend on a timingstrategy that is found via clinical observation to be best for theparticular patient, or may be related to the observed amplitude ofthalamic oscillations or one or more other factors. In one treatmentmode, after stimulation is applied, the system continues to sense datasignals and look for thalamic oscillations and will re-apply stimulationwhen the amplitude threshold is again exceeded.

In an embodiment of the invention, the level of stimulation provided tothe PVG (or the motor cortex, or other neural tissue) is modulated by acharacteristic of observed thalamic oscillations such as amplitude,duration, frequency, or time since prior occurrence. Accordingly, then,after signals are detected, and while they are ongoing, the level oftherapy (including possible changes to stimulation amplitude, pulsewidth, or frequency) applied is controlled to minimize the observedoscillations (and the patient's corresponding symptoms of pain). Thecorrelation between stimulation level and observed magnitude of the painsignature is not necessarily linear; some patient-specific clinicalobservation and measurement or real-time feedback control of the therapysubsystem 424 is recommended.

It will be appreciated that the foregoing exemplary treatment strategymay only treat part of the pain, e.g. the affective component of centralpain. Accordingly, it may also be effective to provide other stimulationin connection with the PVG stimulation to treat additional components orto provide further relief in the same components. For example, motorcortex stimulation in or near the portion of the cortex responsible forthe portion of the body where pain is experienced may also bestimulated. This stimulation may be provided in a manner that isresponsive to the same signatures as the PVG stimulation (i.e., certaintypes or frequencies of thalamic oscillations), it may be responsive toa different condition as described elsewhere in this description, or itmay be provided continuously, intermittently, or on a timed program.Multiple stimulation electrodes can be used to cover a larger portion ofthe motor cortex if it is deemed clinically advantageous.

In cases of severe chronic nociceptive pain, such as cancer pain,arthritis pain, or post-surgical pain, an embodiment of the inventionusing at least two modules (a centrally implanted master device moduleand a remote peripherally-located sensor module, though in analternative embodiment of the invention a single module can be used)senses activity in the patient's peripheral nerves and provideselectrical stimulation therapy to the brain in the thalamus,periaqueductal gray matter, periventricular gray matter, and/or motorcortex. The central (e.g., cranially implanted) master device is coupledvia leads and electrodes to the stimulation sites in the brain. Theremote sensor module receives signals from one or more nerves near thesource of the pain to detect abnormal activity. In practice, abnormalactivity in the peripheral nervous system is in many cases representedby a change in the frequency of spikes or impulses observed therein.Large fibers are approximately 3-20 micrometers (μm) in diameter so itis generally practical to measure aggregate activity from nerve bundles,or in an embodiment, individual or small numbers of action potentialsusing a microelectrode.

In cases of phantom limb pain, one or two modules are used to sensesignals in the brain and spinal cord. In an embodiment of the invention,pain signatures are the abnormal activity representative of activationin the primary somatosensory cortex. This activity is measured andstimulation is responsively provided to the periaqueductal orperiventricular gray matter and the motor cortex.

Allodynia, a hypersensitivity to innocuous stimuli (light touch, drafts,etc.) often present in central pain, has some unique characteristics notoften observed in other forms of chronic pain. In particular, a decreasein activation and cerebral blood flow is often observed in the cingulategyms. This activity can be measured by the invention, by sensingelectrical activity related to reduced activation (and hence reducedsignal levels and complexity as may be measured by the waveform analyzerand reflected, for example, in reduced magnitude of higher frequencyspectral components, or reflected in Hjorth parameters of a periodogramincluding first and second derivatives of selected bands) or directmeasurement of cerebral blood flow by temperature, optical, orplethysmographic means. Such activity is also correlated with increasedactivity in the thalamus, insular cortex, and secondary somatosensoryarea. Stimulation may be applied to the thalamus orperiaqueductal/periventricular gray and may be adjusted or initiatedresponsively to the sensed pain signatures.

Dysesthesia, a burning sensation present in central pain, is subject toslow summation. That is, the intensity of the pain is correlated withits duration, and the pain tends to build up over time. Accordingly,detection and treatment of the invention, on a selective andintermittent basis, is particularly advantageous, particularly when bothsensory and affective components are targeted. Dysesthesia is modulated,in an embodiment of the invention, by monitoring activity in thesecondary somatosensory cortex, cingulate gyms, prefrontal cortex,and/or insular cortex, and applying responsive therapy to the thalamus,periaqueductal gray matter, periventricular gray matter, precentralgyms, and as necessary in the cingulate gyms to control the cognitivecomponent of the pain.

Tinnitus, recognized by some researchers to be a form of chronic pain,can be sensed in the patient's auditory cortex, cingulate gyms, andother brain structures associated with affective pain. Inappropriatesensed activity may be terminated by applying responsive, intermittenttherapy to the auditory cortex, brainstem, or thalamus or/and other deepbrain structures and their ascending pathways.

The foregoing scenarios are considered illustrative but are notlimiting.

Considered more generally, it has been observed that pain symptomsfrequently correlate with abnormal activation patterns in various partsof the patient's brain. Imaging techniques such as magnetic resonanceimaging (MRI) can identify structural abnormalities, and functional MRI(fMRI), positron emission tomography (PET), single photon emissioncomputed tomography (SPECT), and various forms of neurospectroscopyincluding magnetic resonance spectroscopy (MRS), near infraredspectroscopy (NIRS), and proton neurospectroscopy can be used toidentify activation patterns and target those areas according to theinvention for either sensing (which may be deployed to measure cerebralblood flow or oxygenation, or more typically is electrographic innature) or therapy. Patient-specific template generation on the basis ofcollected electrographic (and other sensor signal) data, as describedabove, would be used to “tune” the detection capabilities of the deviceto a patient's specific detection needs, define signatures of thepatient's pain, and provide mapping of the physiological measurementsonto their related symptoms in order to determine the physiologicalchanges that correspond to symptoms such as the magnitude of subjectivepain.

With regard to treatment options outside of the guidelines and scenariosset forth above, clinical experience on a patient-by-patient basisprovides guidance as to whether activating or inhibiting a targetlocation may provide relief to the patient, and trends may be observedover populations of patients having similar symptoms and reactions totherapy according to the invention.

Effective treatment of pain according to the present invention may, overthe course of time and through the effects of neuroplasticity, cause thepatient's nervous system to eventually “unlearn” its dysfunctionalpatterns in central pain, and stimulation may be discontinued with noresumption in symptoms.

Returning now to the components of a system according to the invention,an exemplary remote sensor module 610 according to the invention isillustrated in FIG. 6. In the disclosed embodiment, the remote sensormodule 610 includes a number of the same subsystems found in a masterimplantable device such as the device 110. Specifically, as disclosed,two sensors 612 and 614 (which may be electrodes or other types ofsensors as described elsewhere in this document) are coupled to a sensorinterface 616, which in turn is coupled to a detection subsystem 618. Inaddition to detecting characteristics of the sensed signal related topain, the detection subsystem 618 can also function to classify thesensed signals, or can provide a score or index based upon signalprocessing of the one or more signals detected at each sensor. Signalprocessing can include, for example, filtering, pattern recognition,peak detection, spectral and period analysis, regression, prediction,and classification schemes related to evaluating the sensed signal andselecting appropriate responsive neurostimulation treatment parameters.The detection subsystem 618 can also be used to generate or modify thestimulation therapy using control laws, which may comprise one or morelinear or non-linear transfer functions, may contain step functions, maybe altered based upon evaluation of one or more characteristics of thesensed signal. The detection subsystem 618 can obtain reference valuesfrom the memory subsystem 620 related to self-norms, and can storeresults of its operations in the memory subsystem for later reference.Although two sensors are shown for simplicity of illustration (and apotentially advantageous reduction in complexity), any number would bepossible in a remote sensor module according to the invention. Theremote sensor module 610 also includes a memory subsystem 620, a CPU622, a communication subsystem 624, a power supply 626, and a clocksupply 628. The components of the remote sensor module 610 performgenerally the same functions as the corresponding components of thefully featured implantable device 110 (FIG. 4), but the CPU 622 isspecifically configured to operate the remote sensor module 610 inconjunction and in a coordinated fashion with the device 110.

Preferably, and consistent with the description set forth above, theremote sensor module 610 is capable of performing event detectionindependently from other devices, and rather than applying therapydirectly, communicating information representative of event detectionvia the communication subsystem 624 to the device 110, therebyfacilitating inter-device coordination. The coordination process will bedescribed in further detail below.

An exemplary remote therapy module 710 according to the invention isillustrated in FIG. 7. As with the remote sensor module 610 (FIG. 6),the remote therapy module 710 shares components and subsystems with thefully featured implantable device 110 (FIG. 4), and like-namedcomponents serve similar functions. Accordingly, then, the illustratedembodiment of the remote therapy module 710 includes two electrodes 712and 714 coupled to a therapy interface 716. The therapy interface 716 isalso coupled to a drug dispenser 718, which may be disposed within theremote therapy module 710 or alternatively positioned elsewhere for easein refilling one or more drug reservoirs within the dispenser 718. Ineither case, the drug dispenser 718 is coupled to a catheter 720 withits distal end positioned at an advantageous location for therapy, whichmay be either in the central nervous system or peripherally. The remotetherapy module 710 also includes a therapy subsystem 722, a memorysubsystem 724, a CPU 726, a communication subsystem 728, a power supply730, and a clock supply 732.

As described above, the remote therapy module 710 is equipped with anoptical stimulator 734 and a fiber optic lead 736, enabling opticalstimulation of neural structures in the brain, spinal cord, and nerves.Alternatively, the optical stimulator 734 can simply serve to routeoptical signals generated externally to the remote therapy module 710,but which are fed into the unit. Alternatively, due to issues of powerconsumption and storage space, the entire optical stimulator 734 can bea separate module.

The remote therapy module 710 is configured to receive commands from amaster device such as the device 110 (FIG. 4). Accordingly, it has nosensing and detection capabilities of its own; rather, it is driven bycommands and scheduling information received from the master device viathe communication subsystem 728. Commands relating to responsivetherapies are typically provided in real time, whereas therapy schedulesmay be communicated in advance and stored by the remote therapy module710. As will be described below, this enables coordination between anymaster device and remote therapy modules according to the invention.Alternatively, the remote therapy module 710 is configured to workalone, or in combination with a master device 110, but no communicationsubsystem 728 is present and coordinated stimulation occurs merely dueto the real-time clock 732.

It is possible for remote modules to be activated and deactivated by themaster device, thereby saving energy. For example, in one embodiment ofthe invention, a remote sensor module can be activated (i.e., broughtout of a “sleep” mode) by a signal from its communication subsystem. Thecontinuously enabled sleep mode is a default low-power mode in which themodules can still receive commands from the master device 110. Only whenthe master neurostimulator device 110 identifies a potential conditionthat requires corroboration from the remote module, does it send acommand to bring it out of sleep mode. That condition is eitherconfirmed, ruled out, or responded to, and the remote module issubsequently returned to a “sleep” mode. This mode of operation will bedescribed in further detail below. It is also possible that the energyrequirements of sleep mode can be further decreased by having the remotemodules “wake up” periodically (e.g., every 10 minutes) and communicatewith the master device and determine if there is a potential conditionthat requires corroboration.

It will be recognized that a system according to the invention employingmultiple modules capitalizes on an improved ability to sense signals inone portion of the patient's body and deliver therapy elsewhere. This isfacilitated by the use of remote modules as described above, but the useof such modules is not necessary. It is possible to use a single devicein an embodiment of the invention, with multiple leads to reach multipledetection and therapy targets in the body. However, remote modules dofacilitate combination therapies, with stimulation and drugs being usedin different areas to maximum effect.

FIG. 8 illustrates details of the detection subsystem 422 (FIG. 4).Inputs from the sensors 412, 414, 416 and 418 are on the left, andconnections to other subsystems are on the right. It should also benoted that the description of the detection subsystem illustrated inFIG. 8 also applies to the detection subsystem 422 of FIGS. 4 and 618 ofFIG. 6, with appropriate changes as necessary in a remote sensor module610 as would be appreciated by a practitioner of ordinary skill in theart.

Signals received from the sensors 412, 414, 416 and 418 (as routedthrough the sensor interface 420) are received in an input selector 810.The input selector 810 allows the device to select which electrodes orother sensors (of the sensors 412, 414 416 and 418) should be routed towhich individual sensing channels of the detection subsystem 422, basedon commands received through a control interface 818 from the memorysubsystem 426 or the CPU 428 (FIG. 4). Preferably, when electrodes areused for sensing, each sensing channel of the detection subsystem 422receives a bipolar signal representative of the difference in electricalpotential between two selectable electrodes. Accordingly, the inputselector 810 provides signals corresponding to each pair of selectedelectrodes to a sensing front end 812, which performs amplification,analog to digital conversion, and multiplexing functions on the signalsin the sensing channels. When each electrode or sensor has two or moreselectable contacts, each of which can communicate independently withthe device 110 via the input selector, then the difference betweencontacts rather than electrodes may be measured.

A multiplexed input signal representative of all active sensing channelsis then fed from the sensing front end 812 to a waveform analyzer 814.The waveform analyzer 814 is preferably a special-purpose digital signalprocessor (DSP) adapted for use with the invention, or in an alternativeembodiment, may comprise a programmable general-purpose DSP. It may alsohave specialized analog circuitry such as filters, control circuitry,and circuitry for creating stimulation waveforms from the sensed signalusing control laws. In the disclosed embodiment, the waveform analyzerhas its own scratchpad memory area 816 used for local storage of dataand program variables when signal processing or statistics are beingperformed. In either case, the signal processor performs suitablemeasurement, classification, and detection methods described generallyabove and in greater detail below. Any results from such methods, aswell as any digitized signals intended for storage, analyses, control,or transmission to external equipment, are passed to various othersubsystems of the device 110, including the memory subsystem 426 and theCPU 428 (FIG. 4) through a data interface 820. Similarly, the controlinterface 818 allows the waveform analyzer 814 and the input selector810 to be in communication with the CPU 428. The waveform analyzer 814is illustrated in detail in FIG. 10.

In one embodiment, the inputs from the sensors 412, 414, 416 and 418receive signals from different sensors located to sense from differentlocations which are either related to the sensation of pain (Sp) ormostly not related to, or affected by, the sensation of pain (Sn). Spand Sn may be two or more regions of the somatosensory cortex, may be ina structure such as the thalamus, may be contra-lateral structures,and/or may be located in two different brain structures. Thecharacteristics of the pain signature sensed from the Sp region may becompared to a specified threshold, a self-norm, spectral power at otherfrequencies, or spectral power of signals obtained by other sensors thatsense at non-pathological regions (Sn) of the cortex or regions of thethalamus or other brain structures. For example, when sensors arelocated to sense from several regions of the somatosensory cortex, theEEG for an electrode located more proximal to a region related to painperception (EEGp) can be compared to the EEG of neighboring electrodes(EEGn) in order to detect a relevant pain signature. The ratio ofspectral power of selected bands of the EEGp and EEGn signals could beused. Alternatively, coherence computed between EEGp and EEGn can becompared to coherence of one or more spectral bands computed for two ormore EEGn's. The signal from the Sp region can, itself, be used tocompute an index or score using either linear or non-linear measurementschemes, so that this value reflects a pain signature related to aneurophysiological or behavioral symptom of the pain. Alternatively, thesignal from the Sp region can be compared to the signals from the Snregions in order detect a pain signature, as may occur when a specificdifference is found between the signals sensed from the Sp and Snregions. The sensed signals can be obtained from ongoing activity of thebrain or can be obtained in a time period immediately followingstimulation either at the same location as the sensor or at a differentlocation (i.e., the signals can be an evoked response to appliedelectrical, sensory, or other type of stimulation). In order to reducecomputational needs, each of the signals can be routed to one or moreanalog or digital filters. The filters can be arranged in parallel inorder to obtain several spectral estimates from the same signal, or canbe arranged in series with routing to the ADC at different stages offiltering. Various combinations of filtering schemes will providedifferent advantages as is known to those skilled in the art. The filtercharacteristics can be pre-set or can be changed according to thesubject's profile. For example, in order to easily obtain an estimate ofan oscillation related to a pain symptom, the EEG signals from Sp and Snregions can each be filtered by a narrow band filter and thenintegrated. The relative power between the two signals can be comparedin order to derive the pain signature.

Referring now to FIG. 9, the sensing front end 812 (FIG. 8) isillustrated in further detail. As shown, the sensing front end includesa plurality of differential amplifier channels 910, each of whichreceives a selected pair of inputs from the electrode selector 810. In apreferred embodiment of the invention, each of the differentialamplifier channels 910 is adapted to receive or to share inputs with oneor more other differential amplifier channels 910 without adverselyaffecting the sensing and detection capabilities of a system accordingto the invention. Specifically, in an embodiment of the invention, thereare at least eight electrodes, which can be mapped separately to eightdifferential amplifier channels 910 representing eight different sensingchannels and capable of individually processing eight bipolar signals,each of which represents an electrical potential difference between twomonopolar input signals received from the electrodes and applied to thesensing channels via the electrode selector 810. For clarity, only fivechannels are illustrated in FIG. 9, but it should be noted that anypractical number of sensing channels may be employed in a systemaccording to the invention.

As set forth above, activity of interest occurs primarily above 0.1-0.2Hz. Accordingly, the amplifier channels illustrated above can beequipped with high-pass filters to reject lower-frequency activity andDC signal components that might otherwise confound the detectioncapabilities of a system according to the invention. More than one stageof filtering and amplification may take place within each differentialamplifier channel. Preferably, each amplifier is equipped with at leastone band-pass filter and more preferably both filter and gain settingsof the amplifier are programmable.

Each differential amplifier channel 910 feeds a corresponding analog todigital converter (ADC) 912. Preferably, the analog to digitalconverters 912 are separately programmable with respect to samplerates—in the disclosed embodiment, the ADCs 912 convert analog signalsinto 10-bit unsigned integer digital data streams at a sample rateselectable between 250 Hz and 500 Hz. In several of the illustrationsdescribed below where waveforms are shown, sample rates of 250 Hz aretypically used for simplicity. However, the invention shall not bedeemed to be so limited, and numerous sample rate and resolution optionsare possible, with tradeoffs known to individuals of ordinary skill inthe art of electronic signal processing. When measuring signals havingpower at less than 1 Hz, even a sampling rate of 50 Hz is more thansufficient. The resulting digital signals are received by a multiplexer914 that creates a single interleaved digital data stream representativeof the data from all active sensing channels. As will be described infurther detail below, not all of the sensing channels need to be used atone time, and it may in fact be advantageous in certain circumstances todeactivate certain sensing channels to reduce the power consumed by asystem according to the invention.

It should be noted that as illustrated and described herein, a “sensingchannel” is not necessarily a single physical or functional item thatcan be identified in any illustration. Rather, a sensing channel isformed from the functional sequence of operations described herein, andparticularly represents a single electrical signal received from anypair or combination of electrodes, as preprocessed by a system accordingto the invention, in both analog and digital forms. See, e.g., U.S. Pat.No. 6,473,639 to Fischell et al. for “Neurological Event DetectionProcedure Using Processed Display Channel Based Algorithms and DevicesIncorporating These Procedures” issued Oct. 29, 2002, which is herebyincorporated by reference as though set forth in full herein. At times(particularly after the multiplexer 914), multiple sensing channels areprocessed by the same physical and functional components of the system;notwithstanding that, it should be recognized that unless thedescription herein indicates to the contrary, a system according to theinvention processes, handles, and treats each sensing channelindependently.

In the exemplary waveform analyzer illustrated in FIG. 10, theinterleaved digital data stream representing information from all of theactive sensing channels is first received by a channel controller 1010.The channel controller applies information from the active sensingchannels to a number of wave morphology analysis units 1012 and windowanalysis units 1014. It is preferred to have as many wave morphologyanalysis units 1012 and window analysis units 1014 as possible,consistent with the goals of efficiency, size, and low power consumptionnecessary for an implantable device. In a presently preferred embodimentof the invention, there are sixteen wave morphology analysis units 1012and eight window analysis units 1014, each of which can receive datafrom any of the sensing channels of the sensing front end 812 (FIG. 8),and each of which can be operated with different and independentparameters, including differing sample rates, as will be discussed infurther detail below. As indicated specifically in parts of thisspecification, the characteristics measured from signals of differentsensing channels can be compared and combined when evaluating the painsignatures, or signatures of other disorders which may be treated usingthe implantable stimulation device 110.

Each of the wave morphology analysis units 1012 operates to extractcertain feature information from an input waveform. The wave morphologyanalysis units, in the disclosed embodiment of the invention, areconfigured to detect half waves present in the signal being analyzed. Inparticular, observed half waves exceeding a specified minimum durationand minimum amplitude are deemed “qualified half waves.” If the numberof qualified half waves in a specified time period or “window” exceeds aprogrammed criterion, then the wave morphology analysis unit observingthe condition has made a detection. Preferably, hysteresis is accountedfor in the determination of half wave start and end points, therebyallowing small signal variations to be largely ignored. For moredescription of half wave analysis, see U.S. Pat. No. 6,810,285,referenced elsewhere herein.

Similarly, each of the window analysis units 1014 performs certain datareduction and signal analysis within time windows. In an embodiment ofthe invention, each of the window analysis units calculates “linelength” and “area” values and compares these values to programmablethresholds based on longer-term signal trends (though in an embodimentof the invention, static thresholds may also be used). Generalizing tosome extent, line length is a measure of signal complexity, while areais a measure of signal power. Details on line length and area-baseddetection techniques are also set forth in the U.S. Pat. No. 6,810,285patent.

Output data from the various wave morphology analysis units 1012 andwindow analysis units 1014 are combined via the event detector logic1016. The event detector logic 1016 and the channel controller 1010 arecontrolled by control commands 1018 received from the control interface818 (FIG. 8).

A “detection channel,” as the term is used herein, refers to a datastream including the active sensing front end 812 and the analysis unitsof the waveform analyzer 814 processing that data stream, in both analogand digital forms. It should be noted that each detection channel canreceive data from a single sensing channel; each sensing channelpreferably can be applied to the input of any combination of detectionchannels. The latter selection is accomplished by the channel controller1010. As with the sensing channels, not all detection channels need tobe active; certain detection channels can be deactivated to save poweror if additional detection processing is deemed unnecessary in certainapplications.

In conjunction with the operation of the wave morphology analysis units1012 and the window analysis units 1014, a scratchpad memory area 1016is provided for temporary storage of processed data. The scratchpadmemory area 1016 may be physically part of the memory subsystem 426(FIG. 4) of the device 110 (or a remote sensor or therapy module), oralternatively may be provided for the exclusive use of the waveformanalyzer 814 (FIG. 8). Other subsystems and components of a systemaccording to the invention may also be furnished with local scratchpadmemory, if such a configuration is advantageous.

The waveform analyzer can also consist of specialized DSP and statisticsmodules which permit spectral, temporal, and spectro-temporal analysisof signals to permit quantification, classification, and detection ofpain signatures as has been described in different areas of thisspecification. The waveform analyzer can also use control laws in orderto generate output stimulation signals based upon the sensed signals.For example, narrowband power of a 0.2-0.4 Hz sensed signal can directlydetermine the amplitude or duration of the stimulation signal. Thecontrol laws can be non-linear and step functions, for example, outputstimulation does not occur until the sensed signal is above a specifiedthreshold, and does not increase until the sensed signal is above asecond specified threshold, above which a characteristic of the outputsignal changes according to increases in the power of the sensed signalwhich is understood to be the pain signature which is being detected.

The operation of the event detector logic 1016 is illustrated in detailin the functional block diagram of FIG. 11, in which four exemplarysensing channels are analyzed by three illustrative event detectors.

A first sensing channel 1110 provides input to a first event detector1112. While the first event detector 1112 is illustrated as a functionalblock in the block diagram of FIG. 11, it should be recognized that itis a functional block only for purposes of illustration, and may nothave any physical counterpart in a device according to the invention.Similarly, a second sensing channel 1114 provides input to a secondevent detector 1116, and a third input channel 1118 and a fourth inputchannel 1120 both provide input to a third event detector 1122.

Considering the processing performed by the event detectors 1112, 1116,and 1122, the first input channel 1110 feeds a signal to both a wavemorphology analysis unit 1124 (one of the wave morphology analysis units1012 of FIG. 10) and a window analysis unit 1126 (one of the windowanalysis units 1014 of FIG. 10).

The window analysis unit 1126, in turn, includes a line length analysistool 1128 and an area analysis tool 1130. As described in U.S. Pat. No.6,810,285, referenced and incorporated by reference above, the linelength analysis tool 1128 and the area analysis tool 1130 analyzedifferent aspects of the signal from the first input channel 1110.

Outputs from the wave morphology analysis unit 1124, the line lengthanalysis tool 1128, and the area analysis tool 1130 are combined in aBoolean AND operation 1132 and sent to an output 1134 for further use bya system according to the invention. For example, if a combination ofanalysis tools in an event detector identifies several simultaneous (ornear-simultaneous) types of activity in an input channel, a systemaccording to the invention may be programmed to perform an action inresponse thereto. Details of the analysis tools and the combinationprocesses used in event detectors according to the invention are setforth in U.S. Pat. No. 6,810,285.

In the second event detector 1116, only a wave morphology analysis unit1136 is active. Accordingly, no Boolean operation needs to be performed,and the wave morphology analysis unit 1136 directly feeds an eventdetector output 1138.

The third event detector 1122 operates on two input channels 1118 and1120, and includes two separate detection channels of analysis units: afirst wave morphology analysis unit 1140 and a first window analysisunit 1142, the latter including a first line length analysis tool 1144and a first area analysis tool 1146; and a second wave morphologyanalysis unit 1148 and a second window analysis unit 1150, the latterincluding a second line length analysis tool 1152 and a second areaanalysis tool 1154. The two detection channels of analysis units arecombined to provide a single event detector output 1156.

In the first separate detection channel of the third event detector 1122including wave morphology analysis unit 1140 and window analysis unit1142, outputs from the first wave morphology analysis unit 1140, thefirst line length analysis tool 1144, and the first area analysis tool1146 are combined via a Boolean AND operation 1158 into a firstdetection channel output 1160. Similarly, in the second separatedetection channel of third event detector 1122 including analysis units1148 and 1150, outputs from the second wave morphology analysis unit1148, the second line length analysis tool 1152, and the second areaanalysis tool 1154 are combined via a Boolean AND operation 1162 into asecond detection channel output 1164. In the illustrated embodiment ofthe invention, the second detection channel output 1164 is invertiblewith selectable Boolean logic inversion 1166 before it is combined withthe first detection channel output 1160. Subsequently, the firstdetection channel output 1160 and the second detection channel output1164 are combined with a Boolean AND operation 1168 to provide a signalcomprising the output 1156. In an alternative embodiment, a Boolean ORoperation is used to combine the first detection channel output 1160 andthe second detection channel output 1164.

In one embodiment of the invention, the second separate detectionchannel of the third event detector 1122 (analysis units 1148 and 1150)represents a “qualifying channel” with respect to the first separatedetection channel of the third event detector 1122 (analysis units 1140and 1142). In general, a qualifying channel allows a detection to bemade only when both channels are in concurrence with regard to detectionof an event, or when two events are detected approximately at the sametime. For example, a qualifying channel can be used to indicate when twoseparate conditions are occurring in separate parts of the patient'sbody. To do this, the third input channel 1118 and the fourth inputchannel 1120 are configured to receive signals from separate amplifierchannels coupled to electrodes in separate parts of the patient's brain(e.g., in opposite hemispheres). Accordingly, then, the Boolean ANDoperation 1168 will indicate a detection only when the first detectionoutput 1160 and the second detection output 1164 both indicate thepresence of an event (or, when Boolean logic inversion 1166 is present,when the first detection output 1160 indicates the presence of an eventwhile the second detection output 1164 does not). As will be describedin further detail below, the detection outputs 1160 and 1164 can beprovided with selectable persistence (i.e., the ability to remaintriggered for some time after the event is detected), allowing theBoolean AND combination 1168 to be satisfied even when there is notprecise temporal synchronization between detections on the two channels.

It should be appreciated that the concept of a “qualifying channel”allows the flexible configuration of a device 110 according to theinvention to achieve a number of advantageous results. In addition tothe detection of separate conditions, as described above, a qualifyingchannel can be configured, for example, to detect noise so a detectionoutput is valid only when noise is not present, to assist in deviceconfiguration in determining which of two sets of detection parametersis preferable (by setting up the different parameters in the firstdetection channel and the second detection channel, then replacing theBoolean AND combination with a Boolean OR combination), or to require aspecific temporal sequence of detections (which would be achieved insoftware by the CPU 428 after a Boolean OR combination of detections).There are numerous other possibilities.

The outputs 1134, 1138, and 1156 of the event detectors are preferablyrepresented by Boolean flags, and as described below, provideinformation for the operation of a system according to the invention.For example, the outputs 1134, 1138 and 1156 of the three eventdetectors of a detection subsystem 422 can be routed to a therapysubsystem 424 which uses this information to effect and adjust therapy.The number of outputs which were true can be used to adjust therapy. Ifoutput 1134 is true and 1138 and 1156 are false then the therapydelivered may utilize a signal or duration that is one third that whichwould occur if all the outputs were true, possibly signifying a larger,or at least more global event. Additionally, the outputs 1134, 1138 and1156 can also determine the location of the stimulation, as would occurif the stimulation occurred only in regions where events were detected,or only at locations where events were not detected, as the case may be,depending upon whether responsive therapy is promoting positive ornegative closed-loop feedback, and depending upon whether thestimulation is excitatory or inhibitory to activity in the region towhich it is being applied. The therapy subsystem 424 may also changetherapy it delivers based upon the duration for which one or more eventsare detected. As indicated in FIG. 11, the value from the second eventdetector 1116, can be more than a Boolean result, and may provide avalue relating to a characteristic of the event (e.g., size) to theevent detection subsystem 422 to the other subsystems of the device 110.Although FIG. 11 shows the outputs from the window analysis unit 1126and the wave morphology analysis unit 1124 being fed to a Booleanoperator 1132, the values of these outputs can also be fed to othercircuits, operators, and processes, and can be stored in memory storage.These values are available to other subsystems such as the therapysubsystem 424 which can use the magnitude of these outputs to adjust orcreate stimulation therapy. One manner of using these outputs is tosubmit these to modules of the therapy subsystem 424 that enact controllaws to produce the stimulation treatment. Accordingly, the stimulationprogram (duration, site, and type of stimulation), and the stimulationsignal itself can be determined, in part, by the characteristics of thepain signature which is detected.

While FIG. 11 illustrates four different sensing channels providinginput to four separate detection channels, it should be noted that amaximally flexible embodiment of the present invention would allow eachsensing channel to be connected to one or more detection channels. Itmay be advantageous to program the different detection channels withdifferent settings (e.g., thresholds) to facilitate alternate “views” ofthe same sensing channel data stream. Accordingly, different detectionchannels can use different detection, classification, and measurementschemes. Further, the signal processing settings, such as filtersettings, may be different for the different channels in order toprovide spectral estimates, as has been discussed.

The therapy subsystem 424 of FIG. 4 (and by analogy, the therapysubsystem 722 of FIG. 7) is illustrated in greater detail with referenceto FIG. 12.

Referring initially to the input side (right-hand side) of FIG. 12, thetherapy subsystem includes a control interface 1210, which receivescommands, data, and other information from the CPU 428, the memorysubsystem 426, and the detection subsystem 422 (FIG. 4). The controlinterface 1210 uses the received commands, data, and other informationto control a therapy controller 1212. The therapy controller 1212 isadapted to provide stimulation signals appropriate for application aselectrical stimulation to neurological tissue to treat a patient'ssymptoms, and also to generate control signals for drug pumps, thermalstimulators, and other therapy modalities according to the invention. Asset forth above, the therapy controller 1212 is typically activated inresponse to conditions detected by the detection subsystem 422, but maybe commanded by an external device, and in an embodiment also providessome substantially continuous or scheduled therapy.

The therapy controller 1212 is coupled to an electrical stimulationsignal generator 1214, which in a presently preferred embodiment, allowsdifferent stimulation parameters to be selectively applied to thedifferent sensors 412, 414, 416 and 418, either sequentially orsubstantially simultaneously. The stimulation signal generator 1214receives commands and data from the therapy controller 1212, andgenerates electrical stimulation signals having the desiredcharacteristics that are properly time-correlated and associated withthe correct electrodes, and receives power from a controllable voltagemultiplier 1216 to facilitate the application of a proper voltage andcurrent to the desired neurological tissue. The voltage multiplier 1216is capable of creating relatively high voltages from a battery powersource, which typically has a very low voltage; circuits to accomplishthis function are well known in the art of electronics design (and oneparticular version is set forth in U.S. Pat. No. 6,690,974 to Archer etal. for “Stimulation Signal Generator for an Implantable Device” issuedFeb. 10, 2004, which is hereby incorporated by reference as though setforth in full). The stimulation signal generator 1214 has a plurality ofoutputs, which in the disclosed embodiment are coupled to the sensorinterface 420 (FIG. 4). In various embodiments of the invention, thestimulation signal generator 1214 can perform signal isolation,multiplexing, and queuing functions if the sensor interface 420 does notperform such functions.

The therapy controller 1212 is also coupled to a therapy command output1218. The therapy command output 1218 provides an interface to therapymodalities other than the electrical stimulation provided by theelectrical stimulation signal generator 1214. In particular, in anembodiment of the invention, the therapy command output 1218 is coupledto the thermal stimulator 436, the drug dispenser 438, and the opticalstimulator 444 (FIG. 4).

It should be recognized that while various functional blocks areillustrated in FIG. 12, not all of them might be present in an operativeembodiment of the invention. Furthermore, as with the overall blockdiagram of FIG. 4 and the remote therapy module 710 of FIG. 7, thefunctional distinctions illustrated in FIG. 12, which are presented asseparate functions for clarity and understandability herein, might notbe meaningful distinctions in an implementation of the invention.

Elaborating further upon the drug dispenser 438 (FIG. 4) of the device110 and the drug dispenser 718 of the remote therapy module 710 (FIG.7), its internal functional breakdown is illustrated somewhatschematically in FIG. 13. The drug dispenser 438 receives input througha control interface 1310—this input is generally received from thetherapy subsystem 424 (FIG. 4) and its therapy command output 1218. Thedrug dispenser 438 is capable of interpreting commands from the therapysubsystem 424 and acting accordingly.

The control interface 1310 drives a pump controller 1312 which, from thecommands received and interpreted by the control interface 1310,generates an analog control signal, which in turn controls a releaseapparatus 1314 comprising, in the disclosed embodiment, a pump and oneor more valves. The release apparatus 1314 receives a therapeutic agent(such as a local anesthetic, an analgesic, a corticosterioid, or anopiod) from a reservoir 1316 and delivers the agent through a releasemonitor 1318 to an output device such as the catheter 442. The releasemonitor 1318 precisely measures the amount of agent delivered by thedrug dispenser 438 and provides information back to the pump controller1312, thereby allowing regulation of the quantity of therapeutic agenttransferred from the reservoir 1316. In an alternative embodiment of theinvention, the release monitor may be positioned between the reservoir1316 and the release apparatus 1314, as long as it is still capable ofmeasuring flow volumes accurately. In yet another embodiment, therelease monitor 1318 is not present; the drug dispenser 438 relies uponthe precision of the release apparatus 1314 to control the amount oftherapeutic agent delivered.

An embodiment of the communication subsystem 430 (FIG. 4) is illustratedin FIG. 14; the disclosed embodiment enables several different modes ofcommunication intended for different purposes. It will be appreciatedthat the communication subsystem 430 illustrated in FIG. 14 shares someor all of its components and attributes with the communication subsystem624 for the remote sensor module 610 and the communication subsystem 728for the remote therapy module 710.

The communication subsystem 430 includes a data interface 1410 connectedand configured to exchange data with the CPU 428 or directly with thememory subsystem 426. The data interface 1410 serves as a selector toenable one or more of the available communication modalities providedfor by the invention. The data interface 1410 communicates with acommunication controller 1412 interfacing with at least one but in thedisclosed embodiment a plurality of transducers 1414, 1416, 1418, 1420and 1422. The communication controller 1412 enables message queuing,transducer arbitration, protocol translations, and any other necessarysteps and functions well known in the art of data communications.

As set forth above, a short-range telemetry transducer 1414 in thedisclosed embodiment of the communication subsystem 430 includes atelemetry coil (which may be situated inside or outside of the housingof the implantable neurostimulator device 110) enabling transmission andreception of signals, to or from an external apparatus, via inductivecoupling. Short range telemetry is generally effective over distances ofonly a few centimeters.

An additional transducer provided comprises a long-range telemetrytransducer 1416 with an antenna, enabling longer-range (and potentiallyhigher data rate) communications over an RF link. For an implantabledevice, it is reasonable to expect communication ranges of up to a fewmeters, possibly more. Relay modules which are either implanted orexternal to the device may assist in boosting the range of thecommunication. In an embodiment of the invention, the long-rangetelemetry transducer operates in the MICS (Medical ImplantCommunications Service) band at approximately 402-405 MHz. This band iswell suited for communication within and around the human body and isavailable for use in the United States without a license. MICS deviceshave a very low EIRP (effective isotropic radiated power) limited to 25microwatts, and hence are considered safe. Integrated circuits enablingMICS communication are commercially available; they may be coupled to ashort external pigtail antenna (generally 2-10 cm in length, but otherlengths may be used), an external patch antenna, or a patch or traceintegrated into a header or housing of the device 110. In an alternativeembodiment of the long-range telemetry transducer, aBluetooth-compatible wireless link may be provided.

An audio transducer 1418 is also provided, though in an embodiment ofthe invention the audio transducer may be part of the therapy subsystem424 as described above. As part of the communication subsystem 430, theaudio transducer is capable of generating audio signals that can beheard by the patient (for example, as a warning or a programmingconfirmation), or modulated audio signals (e.g., FSK) for short-rangetelemetry purposes. A piezoelectric device coupled to a housing 226(FIG. 2) of the device 110 is well suited for this. The audio transducerin an embodiment of the invention is also capable of receiving anddecoding modulated audio signals or audio/tactile input from thepatient.

A command transducer 1420 is present, which in the disclosed embodimentof the invention comprises a GMR (giant magnetoresistive effect) sensorto enable receiving simple signals (namely the placement and removal ofa magnet) from a patient initiating device according to the invention.Another embodiment of the command transducer 1420 is pressure sensitive.In either case, this input can be used, for example, to enablepatient-commanded therapy overrides when pain, numbness, tingling, orother symptom of the disorder is particularly severe and automaticresponsive therapy is considered insufficient. This capability isenabled via firmware or software in the device 110. If the therapysubsystem 424 or the communication subsystem 430 includes the audiocapability set forth above, it may be advantageous for the communicationsubsystem 430 to cause an audio signal to be generated upon receipt ofan appropriate indication from the patient initiating device (e.g., themagnet used to communicate with the GMR sensor of the communicationsubsystem 430), thereby confirming to the patient or caregiver that adesired action will be performed.

Finally, an intrabody communication transducer 1422 is available. In anembodiment of the invention, the intrabody communication transducerleverages the capabilities of the long-range telemetry transducer 1416to enable communication between devices in the human body, such asbetween a master device 110 and a remote sensor module 610 (FIG. 6) or aremote therapy module 710 (FIG. 7). The MICS band is also appropriatefor this purpose; as described above, it is suitable for communicationentirely within the body. Alternatively, and somewhat more generally, anear-field electromagnetic radiator and receptor, such as a dipoleantenna, can facilitate the modulation of data onto any carrierfrequency that is advantageously not absorbed by tissues of the humanbody, by means well known in the art. The body between dipole antennasserves as the transmission medium between two implanted devices. Soniccommunication between audio transducers and receivers is also consideredpossible; necessary implementation details would be known and understooda practitioner of ordinary skill in sonic intra-device communications ingeneral.

In general, intrabody inter-device communication is preferably limitedto intermittent exchanges of short messages to limit power usage.Accordingly, each of the remote sensor modules 610 (FIG. 6) has its owndetection subsystem 618 and CPU 622, and each of the remote therapymodules 710 (FIG. 7) is configured with its own therapy subsystem 722and CPU 726, allowing for semi-autonomous operation when messages arenot being exchanged with other devices. However, in an embodiment of theinvention, a remote sensor module 610 or a remote therapy module 710according to the invention may omit much of its internal processing (andmemory) in favor of a more heavily used communication link to a masterdevice where processing and analysis is performed. This coordinationwill be described in further detail below.

A system according to the invention, particularly the neurostimulatordevice 110, is contemplated to be capable of multiple modalities oftherapy. In general, regular or scheduled therapy may be consideredadvantageous at certain times, and may be scheduled to operate inparallel with responsive therapy modes. Moreover, the neurostimulatordevice 110 is also gathering data to perform detection and enabletherapy refinement in connection with the programmer 312 (FIG. 3) andother external equipment. A basic detection process according to theinvention is illustrated in more detail in connection with FIG. 15.

Initially, and continuously, the neurostimulator device 110 measuressensor signals (step 1510) received from the sensors 412, 414, 416 and418. Various types of sensor data, including electrographic signalwaveforms, may be collected by a system according to the invention.Sensors may measure electrographic activity, brain chemistry,temperature, other indicia of physiological conditions and metabolicrate, and patient intent (as indicated by a signal received from thepatient initiating device 324 (FIG. 3). Analogously, in a remote sensormodule 610, sensor signals are measured from the corresponding sensors612,614. The sensor signals are analyzed (step 1512) by the detectionsubsystem 422 and the CPU 428. Generally, custom hardware in thedetection subsystem 422 continuously or semi-continuously monitors thesensor signals and provides an interrupt event to the CPU when activityof interest is occurring, allowing the CPU to “wake up” from a low-powerstate and provide additional processing as needed.

If an event is detected by the CPU (step 1514) according to criteria asdescribed above and illustrated in FIG. 11, an action to be taken inresponse is identified (step 1516) and then performed (step 1518). Theaction may include one or more activities, such as continuing to measure(and not applying therapy), storing a record of sensor data for futureuploading, applying a therapy locally with the therapy subsystem 424,sending a message to external modules (such as the remote therapy module710) to intiate therapy, initiating therapy locally, or adjustingstimulation levels locally or remotely to accommodate changed detectionlevels as described above. The information gathered in measuring (step1510) and analyzing (step 1512) may also be summarized and transmittedto a remote sensor module 610 to confirm detection of an event ofinterest.

As set forth above, the delivery of therapy as an action in FIG. 15 hasan effect that extends beyond the immediate duration of the therapy. Theduration may vary from patient to patient, however, and therapyaccording to the invention may be optimized by applying a dose oftherapy (such as a burst of electrical stimulation) and waiting for theappropriate detection conditions to occur again, or if therapy isongoing, adjusting its level to account for changed detection conditions(e.g., a change in level of the observed thalamic oscillations). In anembodiment of the invention, the device receives input from the patienton the duration of relief and suppresses therapy during that interval.

If no event is detected (step 1514), the device continues (step 1520)and carries on with the measurement (step 1510) and analysis (step 1512)of sensor signals.

Although most of the foregoing description pertains most directly to thedevice 110 illustrated functionally in FIG. 4, it also applies to otherdevices and modules according to the invention capable of measuringsensor signals and detecting events therein. It should further be notedthat the event-driven and parallel processing nature of the device 110allows for other types of functions by the neurostimulator device 110 tobe performed essentially simultaneously with the detection function,such as administrative functions. The nature of these additionalfunctions would be understood by an engineer competent in designingreal-time systems.

Considering the detection and therapy process in more detail, with thecoordination of multiple modules, processes performed by an exemplaryembodiment of the invention using a master device such as theneurostimulator device 110, a remote sensor module 610, and a remotetherapy module 710, are illustrated in FIG. 16.

As in FIG. 15, sensor signals are monitored by the device 110 (step1610) and the remote sensor module 610 (step 1612) essentiallycontinuously, and those signals are analyzed by both the device 110(step 1614) and the remote sensor module 610 (step 1616) as needed. Whenan event of interest is noted in either the device 110 or the remotesensor module 610, inputs relating to the event are coordinated by thedevice 110 (step 1618). In an embodiment of the invention, an eventdetection in a remote sensor module 610 causes the remote sensor module610 to transmit a message via its communication subsystem 624 to thedevice 110. Advantageously, the message may contain information aboutthe detected event (such as its magnitude, location, precise timing, orsome other parameter of interest) but alternatively the messageindicates only that an event occurred.

Coordination of detection inputs as described herein combines andcorrelates the information received from the remote sensor module 610with information obtained from the analysis (step 1614) performedlocally on the master device 110. The combination and correlation, in anembodiment of the invention, comprises a simple Boolean combination ofinputs (event occurs in the master device AND the remote sensor module,or the event occurs in the master device OR the remote sensor module, asconfigured) with a selectable persistence for both detections asdescribed above. In an alternative embodiment, a detection-relatedparameter received from the remote sensor module 610 is combined via amathematical transform, (e.g., multivariate equation), with a parameterobserved by the device 110, and that combination is compared to acriterion to determine whether an event of interest has occurred.Further details will be set forth below in conjunction with FIGS. 17-18.

If such an event has been detected (step 1620), the master device 110identifies the appropriate actions to perform (step 1622) and thoseactions are coordinated among the relevant portions of the system (step1624). In the disclosed embodiment, an action is identified (step 1622)and performed (step 1626) by the master device 110 and an action isidentified (step 1622) and performed (step 1628) by the remote therapymodule 710.

As described above, the step of performing an action (step 1626) mayinclude such as continuing to measure (and not applying therapy),storing a record of sensor data for future uploading, applying a therapylocally with the therapy subsystem 424, sending a message to externalmodules (such as the remote therapy module 710) to initiate therapy,initiating therapy locally, or adjusting (via feedback) stimulationlevels locally or remotely to accommodate changed detection levels.

In coordinating actions to be performed (step 1624), the programming ofthe device 110 preferably considers clinically relevant criteria (e.g.,which may be related to detection of a particular pain signature),including but not limited to the types of therapy that are effective atvarious locations reachable by the modules in use, time synchronizationof multiple therapies (where advantageous), and relief from multiplesymptoms and components of chronic pain and other disorders as describedgenerally above.

Whether or not an event has been detected (step 1620), the device 110continues (step 1630) by measuring sensor signals (step 1610), theremote sensor module 610 continues (step 1632) by also measuring sensorsignals (step 1612), and the remote therapy module 710 continues (step1634) by awaiting further commands from the device 110. It will berecognized that the continuing measurement activities may proceed in anyor all of the modules of the invention while therapy and other actionsare being performed.

For example, in an embodiment of the invention, as described above inconnection with FIG. 5, one or more modules may operate independently orin a coordinated fashion to detect activity and apply therapy inmultiple locations. The scenarios set forth in the context of FIG. 5 areillustrative. Where sensing occurs in a single location and therapy inmultiple locations in the brain, a master device (for processing andtherapy) in conjunction with a remote sensing module may be an effectivecombination of resources, where the master device coordinates therapy.In this manner, different types of therapy may be used by one or moredevices to suppress sensory and affective components of pain. Wheresensing occurs in multiple locations and therapy occurs in multiplelocations, plural remote sensing modules and remote therapy modules maybe coordinated by a single master device, or multiple master devices maybe used independently (without intrabody communication) to independentlytreat multiple symptoms or conditions.

Cognitive effects of pain may be controlled by sensing or providingtherapy in the anterior cingulate gyms, the posterior parietal cortex,or the prefrontal cortex, which tend to be activated when pain isexperienced. Attention, stress, and arousal may tend to modulate thepatient's response to pain.

It will be recognized that it may be advantageous in some circumstancesto employ multiple strategies even for a single component of pain.Multiple pain signatures may be observed and tied to different therapiesusing different devices, stimulation protocols, and stimulation signals.This may occur, in part, using multiple control laws each of whichdictates a type of stimulation based upon sensing of a particular painsignature. The therapies may be coordinated or independent.

A process leading up to coordinating detection inputs (FIG. 16, step1618) is illustrated in additional detail in FIG. 17. The disclosedprocess can be performed by any module of a system according to theinvention having measurement and detection capabilities, including theneurostimulator device 110 (FIG. 1) and the remote sensor module 610(FIG. 6).

Initially, as previously discussed, the device 110 or remote sensormodule 610 measures and analyzes sensor signals, sending data to the CPU428 or 622 (step 1710). If the CPU determines that an event has beenobserved (step 1712), the event is parametrized (step 1714), i.e.,reduced to one or more parameters representing useful information aboutthe event. If the device having received the data and observed the eventis the master device 110 (step 1716), then detection coordination asdescribed above commences (step 1718). Otherwise, the device is a remotemodule such as the remote sensor module 610, and the parameters obtainedfrom the event are transmitted to the master device 110 (step 1720). Ineither case, the device 110 or module 610 continues (step 1722) as setforth above.

A process of coordinating multiple detection inputs by a systemaccording to the invention (FIG. 16, step 1618) is illustrated inadditional detail in FIG. 18. As described elsewhere herein, devicesaccording to the invention are generally event-driven (and morespecifically are interrupt-driven computing devices), therebyfacilitating messaging and synchronization among multiple modules.

A device according to the invention having measurement and detectioncapabilities, including the neurostimulator device 110 (FIG. 1) and theremote sensor module 610 (FIG. 6), initially receives a trigger event(step 1810). If the trigger event is a local event from the detectionsubsystem 422 or the CPU 428 of the device 110 (step 1812), the devicethen requests a measurement from one or more remote modules (such as theremote sensor module 610) by transmitting a measurement command (step1814) and awaiting results (step 1816).

If the trigger event is a remote event (step 1820) received from thecommunication subsystem 430 (and typically originally transmitted by aremote module such as the remote sensor module 610), the device 110 thenobserves local conditions (step 1822).

In both cases, parameters obtained from the local measurement and theremote measurement are combined into an overall metric (step 1824). Asdescribed above, this combination can be a simple Boolean combination,with or without persistence, or may be a mathematical transform of thetwo or more inputs. Additionally, the parameters may be submitted to amodel, algorithm, multivariate equation, classification or patternmatching subroutine, a neural net or to two or more serial or parallelcomputations which may include logical operators: any of these mayresult in one or more metrics, indices, or probabilities. These resultscan be used to determine or adjust the neurostimulation treatment. Theparameters and these results can also be submitted to one or morecontrol laws which can be used to provide neurostimulation at one ormore leads.

One or more combinations, indices, or probabilities are compared to adetection criterion (step 1826), and if that criterion is satisfied, adetection is triggered (step 1828) and the system coordinates actionsaccordingly. These actions can be determined, in part, by thecharacteristics of the event that was detected (such as peak amplitude,duration, or other indicia of severity, for example) and the results ofthe operations and transforms used to evaluate these characteristics.Thereafter, in all cases, the device continues (step 1830), waiting foranother trigger event to occur.

Referring now to FIG. 19, in addition to traditional biphasic pulsewaveforms used for neurostimulation, other wave morphologies may haveadvantageous applications herein. A sinusoidal stimulation signal 1910can be produced and used for non-responsive or responsive brain or nervestimulation according to the invention. In general, sinusoidal andquasi-sinusoidal waveforms may be delivered at low frequencies to havean inhibitory effect, where low frequencies are 0.5 to 10 Hz deliveredfor 0.05 to 60 minutes at a time. Such waveform may be applied as aresult of determining that inhibition is desired on a scheduled basis,or after conditions indicate that responsive stimulation should beapplied. Higher frequency sinusoidal or quasi-sinusoidal waveforms maybe used for activation. Even higher frequency sinusoidal or pulsatilestimulation may tend to simulate the effects of lesioning (butreversibly), more or less blocking the function of the target structure.

Amplitudes in the range of 0.1 to 10 mA would typically be used fornon-pulsatile stimulation (with higher amplitudes possible forshort-pulse biphasic pulsatile stimulation), but attention to safecharge densities is important to avoid neural tissue damage. Aconservative charge density limit for pulsatile stimulation is about 25μC/cm² per phase, but for sinusoidal stimulation the limit is expectedto be considerably higher. It should be noted that the inhibitory andactivating functions of various sinusoidal stimulation parameters mayvary when applied to different parts of the brain; the above is merelyexemplary.

Sinusoidal and quasi-sinusoidal waveforms presented herein would beconstructed digitally by the therapy subsystem 424 (FIG. 4) of theimplantable neurostimulator device 110. As a result, the sinusoid 1910is really generated as a stepwise approximation, via a series of smallsteps 1912. The time between steps is dependent upon the details of thewaveform being generated, but an interval on the order of 40microseconds has been found to be a useful value. It is anticipated thatthe stair step waveform 1912 may be filtered to arrive at a waveformmore similar to 1910, which would allow for longer periods of timebetween steps and larger steps. Likewise, for the waveforms 1918, 1920,1922 and 1924 (described below), it is assumed that they may be createdwith a series of steps notwithstanding their continuous appearance inthe figures.

A truncated ramp waveform 1918 is also possible, where the rate of theramp, the amplitude reached and the dwell at the extrema are allselectable parameters. The truncated ramp has the advantage of ease ofgeneration while providing the physiological benefits of a sinusoidal orquasi-sinusoidal waveform.

A variable sinusoidal waveform 1920 where the amplitude and frequencyare varied while the waveform is applied is also illustrated. The rateand amplitude of the variation may be varied based upon a predefinedplan, or may be the result of the implanted neurostimulator sensingsignals from the brain during application or between applications of thewaveform, and adjusting to achieve a particular change in the sensedsignals. The variable waveform 1820 is illustrated herein as having apositive direct current component, but it should be noted that thiswaveform, as well as any of the others described herein as suitable foruse according to the invention, may or may not be provided with a directcurrent component as clinically desired.

Waveforms 1922 and 1924 depict variations where the stimulating waveformis generated having a largely smooth waveform, but having the additionalfeature where the interval between waveforms is set by varying aselectable delay, as would be used with the traditional biphasic pulsewaveforms described previously. In waveform 1922, the stimulatingwaveforms are segments of a sine wave separated in time (of course, thesame technique could be used for the truncated ramp, or other arbitrarymorphologies). Waveform 1924 shows a variation where the derivative intime of the waveform approaches zero as the amplitude approaches zero.The particular waveform 1924 is known as a haversine pulse.

Although the term “haversine pulse” is useful to describe the waveformof 1924, it should be noted that all of the waveforms represented inFIG. 19 are considered herein to be generally “non-pulsatile,” incontrast with waveforms made up of traditional discontinuous (e.g.square) pulses. As the term is used herein, “non-pulsatile” can also beapplied to other continuous, semi-continuous, discontinuous, or stepwiseapproximated waveforms that are not exclusively defined by monophasic orbiphasic square pulses.

In the disclosed embodiment, the default stimulation behavior providedby a neurostimulator according to the invention is to stimulate withcharge-balanced biphasic pulses. This behavior is enforced bystimulation generation hardware that automatically generates a symmetricequal-current and equal-duration but opposite-polarity pulse as part ofevery stimulation pulse; the precise current control enabled by thepresent invention makes this approach possible. However, theneurostimulator is preferably programmable to disable the automaticcharge balancing pulse, thereby enabling the application of monophasicpulses (of either polarity) and other unbalanced signals.

Alternatively, if desired, charge balancing can be accomplished insoftware by programming the neurostimulator to specifically generatebalancing pulses or signals of opposite phase. Regardless of whethercharge balancing is accomplished through hardware or software, it is notnecessary for each individual pulse or other waveform component to becounteracted by a signal with identical morphology and opposingpolarity; symmetric signals are not always necessary. It is alsopossible, when charge balancing is desired, to continuously orperiodically calculate the accumulated charge in each direction andensure that the running total is at or near zero over a relatively longterm and preferably, that it does not exceed a safety threshold even fora short time.

To minimize the risks associated with waveforms that are eitherunbalanced or that have a direct current component, it is advantageousto use electrodes having enhanced surface areas. This can be achieved byusing a high surface area material like platinum black or titaniumnitride as part or all of the electrode. Some experimenters have usediridium oxide advantageously for brain stimulation, and it could also beused here. See Weiland and Anderson, “Chronic Neural Stimulation withThin-Film, Iridium Oxide Electrodes,” IEEE Transactions on BiomedicalEngineering, 47: 911-918 (2000).

An implantable version of a system according to the inventionadvantageously has a long-term average current consumption on the orderof 10 microamps, allowing the implanted device to operate on powerprovided by a coin cell or similarly small battery for a period of yearswithout need for replacement. It should be noted, however, that asbattery and power supply configurations vary, the long-term averagecurrent consumption of a device according to the invention may also varyand still provide satisfactory performance.

It should be observed that while the foregoing detailed description ofvarious embodiments of the present invention is set forth in somedetail, the invention is not limited to those details and an implantableneurostimulator device or system made according to the invention candiffer from the disclosed embodiments in numerous ways. In particular,it will be appreciated that embodiments of the present invention may beemployed in many different applications to responsively treat variouspain disorders and both acute and chronic pain conditions as well asadjunct symptoms that arise due to the disorder. It will be appreciatedthat the functions disclosed herein as being performed by hardware andsoftware, respectively, may be performed differently in an alternativeembodiment. It should be further noted that functional distinctions aremade above for purposes of explanation and clarity; structuraldistinctions in a system or method according to the invention may not bedrawn along the same boundaries. Hence, the appropriate scope hereof isdeemed to be in accordance with the claims as set forth below.

1. An implantable apparatus for treating pain in a human patient byselectively applying therapy, the apparatus comprising: a therapysubsystem coupled to at least one therapy output, wherein the therapysubsystem is operative to selectively initiate delivery of a therapy tothe therapy output; a detection subsystem coupled to at least onesensor, wherein the detection subsystem is operative to receive andprocess a signal generated by the sensor; and a processor operative toidentify a pain signature in the sensor signal and to cause the therapysubsystem to initiate application of the therapy in response thereto,wherein the pain signature represents at least two pain componentsselected from the group of sensory pain, affective pain, and cognitivepain.
 2. The implantable apparatus of claim 1, wherein a first one ofthe at least one sensors is located at or near a detection locationselected from a primary somatosensory cortex, a secondary somatosensorycortex, an anterior cingulate cortex, a prefrontal cortex, an insularcortex, a thalamus, a spinal cord, or a peripheral nerve of the humanpatient.
 3. The implantable apparatus of claim 2, wherein the painsignature comprises a pattern occurring in the detection location. 4.The implantable apparatus of claim 1, wherein the pain signaturecomprises an electrical burst in the thalamus.
 5. The implantableapparatus of claim 1, wherein the pain signature comprises anelectrographic pattern indicative of activation.
 6. The implantableapparatus of claim 1, wherein the pain signature comprises anelectrographic pattern indicative of inhibition.
 7. The implantableapparatus of claim 1, wherein the pain signature comprises anoscillating signal observed in the thalamus.
 8. The implantableapparatus of claim 7, wherein the oscillating signal has a frequencybetween approximately 0.1 Hz and approximately 1.0 Hz.
 9. Theimplantable apparatus of claim 7, wherein the oscillating signal has afrequency between about 0.2 Hz and 0.4 Hz.
 10. The implantable apparatusof claim 7, wherein a first one of the at least one sensors is implantedin a ventroposterolateral thalamic nucleus.
 11. The implantableapparatus of claim 1, wherein a first one of the at least one therapyoutputs comprises an electrical stimulation electrode, a cathetercoupled to a drug dispenser, or a thermal conductor coupled to a thermalstimulator.
 12. The implantable apparatus of claim 1, wherein a firstone of the at least one therapy outputs is located at a therapy locationselected from a thalamus, a motor cortex, a brain stem structure, aperiaqueductal gray area, a periventricular gray area, a precentralgyms, or a parietal cortex of the human patient.
 13. The implantableapparatus of claim 12, wherein the therapy location is patient specific.14. The implantable apparatus of claim 1, wherein the implantableapparatus comprises a plurality of detection channels.
 15. Theimplantable apparatus of claim 14, wherein each of the plurality ofdetection channels is capable of being operated independently from everyother detection channel.
 16. The implantable apparatus of claim 1,wherein the at least one therapy output comprises a plurality of therapyoutputs.
 17. The implantable apparatus of claim 16, wherein each of theplurality of therapy outputs is capable of being controlledindependently from every other therapy output.
 18. The implantableapparatus of claim 1, wherein the implantable apparatus comprises amaster device.
 19. The implantable apparatus of claim 18, wherein theimplantable apparatus further comprises a remote sensing module.
 20. Theimplantable apparatus of claim 18, wherein the implantable apparatusfurther comprises a remote therapy module.
 21. The implantable apparatusof claim 1, wherein the pain comprises nociceptive pain.
 22. Theimplantable apparatus of claim 1, wherein the pain comprises neuropathicpain.
 23. The implantable apparatus of claim 1, wherein the paincomprises psychogenic pain.
 24. The device of claim 1, wherein a firstone of the at least two pain components includes a central aspect, aperipheral aspect, or an idiopathic aspect.
 25. The device of claim 1,wherein the pain signature arises from a nociceptive pain, a neuropathicpain, or neurogenic pain experienced by the patient.
 26. The device ofclaim 1, further comprising a therapy management component adapted tocontrol the therapy subsystem according to at least one control law. 27.The device of claim 26, wherein the therapy management component iscoupled to receive input from at least one of the processor and thedetection subsystem.
 28. The implantable apparatus of claim 1, whereinthe at least one therapy output comprises an electrical stimulationelectrode, a magnetic stimulator, a transcranial magnetic stimulator, anoptical stimulator, a catheter coupled to a drug dispenser, or a thermalconductor coupled to a thermal stimulator.
 29. The implantable apparatusof claim 28 wherein the at least one therapy output comprises aplurality of therapy outputs, wherein each of the plurality of therapyoutputs is capable of being controlled independently from every othertherapy output.
 30. The implantable apparatus of claim 29, wherein eachof the therapy outputs is positioned and programmed to treat a paincomponent.
 31. The implantable apparatus of claim 29, wherein a firstone of the at least two pain components includes a central aspect, aperipheral aspect, or an idiopathic aspect, and wherein each of thetherapy outputs is positioned and programmed to treat an aspect of thefirst one of the at least two pain components.
 32. The implantableapparatus of claim 1, wherein the processor is further operative toidentify a pain signature in the sensor signal based on the spectralcharacteristics of the sensor signal.
 33. An implantable apparatus fortreating neuropathic pain in a human patient by selectively applyingtherapy, the apparatus comprising: a therapy subsystem coupled to atleast one therapy output located at a therapy location selected from athalamus, a motor cortex, a brain stem structure, a periaqueductal grayarea, a periventricular gray area, a precentral gyms, or a parietalcortex of the human patient, wherein the therapy subsystem is operativeto selectively initiate delivery of a therapy to the at least onetherapy output; a detection subsystem coupled to at least one sensorlocated at or near a detection location selected from a primarysomatosensory cortex, a secondary somatosensory cortex, an anteriorcingulate cortex, a prefrontal cortex, an insular cortex, a thalamus, aspinal cord, or a peripheral nerve of the human patient, wherein thedetection subsystem is operative to receive and process a signalgenerated by the sensor; and a processor operative to identify a painsignature in the sensor signal based on spectral characteristics of thesensor signal and to cause the therapy subsystem to initiate applicationof the therapy in response thereto.